KR20010033990A - Matrix Metalloprotease Inhibitors - Google Patents

Abstract

Compounds of formula (I) or pharmaceutically acceptable salts thereof or solvates thereof, wherein the substituents have the values described herein, are useful as inhibitors of the matrix metalloprotease (MMP).

Description

Matrix Metalloprotease Inhibitors

The present invention relates to certain compounds and pharmaceutically acceptable salts thereof which inhibit matrix metalloproteases (MMPs), in particular MMP-3, MMP-12 and MMP-13. Thus, they are useful for treating mammals in conditions that can be alleviated by inhibiting MMPs, in particular MMP-3, MMP-12 and MMP-13.

MMPs, as part of general physiological methods and pathological conditions, make up a group of structurally similar zinc-containing metalloproteases that are involved in the remodeling, repair and degradation of extracellular matrix proteins. Since they have a high breaking potential, MMPs often exist under closed control, and MMP control failures are involved as a factor of many states. Examples of conditions in which MMPs are considered important include bone reconstruction, implantation of the embryo in the uterus, infiltration of immune cells into the site of inflammation, ovulation, spermatogenesis, tissue remodeling and organ differentiation during lesion repair, such as venous and diabetic ulcers. , Bedsores, colon ulcers, for example ulcerative colitis and Crohn's disease, duodenal ulcers, fibrosis, local invasion to adjacent areas of the tumor, metastatic spread of tumor cells from the first site to the second site and tissue destruction in arthritis, Dermatological diseases such as dystrophic bullous epidermal detachment, herpes dermatitis or conditions caused or exacerbated by embolic phenomena such as chronic or acute heart or cerebral infarction.

Conditions involving MMP-3 and MMP-13 include tissue destruction, eg, venous and diabetic ulcers, pressure sores, colon ulcers, for example tissue destruction in ulcerative colitis and Crohn's disease, duodenal ulcers and arthritis, skin diseases, eg For example, conditions caused or exacerbated by dystrophic bullous epidermal detachment, herpes dermatitis or embolic events, such as chronic or acute heart or cerebral infarction.

Another important function of certain MMPs is to activate other enzymes, including other MMPs, by isolating the pro-domain from the protease domain. Thus, since certain MMPs act to regulate the activity of another MMP, overproduction of one MMP may cause excessive proteolysis of the extracellular matrix by the other.

Excessive production of MMP-3 is believed to cause pathological tissue breakdown that underlies numerous diseases and conditions. For example, since MMP-3 is found in the synovial membrane and cartilage of patients with osteoarthritis and rheumatoid arthritis, MMP-3 is involved in joint damage caused by this disease (KL Sirum, CE Brinkerhoff, Biochemistry , 1989, 28, 8691; Z. Gunja-Smith, H. Nagasse, JF Woessner, Biochem. J., 1989, 258, 115). MMP-13 is also believed to play an important role in the pathology of osteoarthritis and rheumatoid arthritis (M. Stahle-Backdahle, B. Sandstedt, K. Bruce, A. Lindahl, MG Jimenez, JA Vega, C. Lopez Otin, Lab. Invest., 1997, 76, 717-28; O. Lindy, YT Konttinen, T. Sorsa, Y. Ding, S. Santavirta, A. Ceponis, C. Lopez Otin, Arthritis Rheum. 1997, 40, 1391-9).

Over-expression of MMP-3 is also believed to be responsible for many tissue damage and chronic lesions of chronic lesions, such as venous and diabetic ulcers and pressure sores (M. Vaalamo, M. Weckroth, P. Puoakkainen). , J. Kere, P. Saarinen, J. Lauharanta, UK Saarialho-Kere, Brit. J. Dermatology, 1996, 135, 52-59).

During the healing of normal and chronic lesions, MMP-1 is expressed by keratinocyte migration in the lesion edge (UK Saarialho-Kere, SO Kovacs, AP Pentland, J. Clin. Invest. 1993, 92, 2858 -66]. Keratinocyte migration on collagen type I matrix in vitro requires MMP-1 and the non-selective MMP inhibitor SC44463 ((N4-hydroxy) -N1-[(1S) -2- (4-methoxyphenyl) methyl- There is evidence suggesting that it is completely inhibited by the presence of 1-((1R) -methylamino) carbonyl)]-(2R) -2- (2-methylpropyl) butanediamide) (BK Pilcher, J, A, Dumin, BD Sudbeck, SM Krane, HG Welgus, WC Parks, J. Cell Biol., 1997, 137, 1-13). In vitro keratinocyte migration is essential to effectively heal the affected area.

MMP-2 and MMP-9 appear to play an important role in wound healing during the extended remodeling phase and the onset of re-epithelialization, respectively (MS Agren, Brit. J. Dermatology, 1994, 131, 634-40 T. Salo, M. Maekaenen, M. Kylmaeniemi, Lab, Invest., 1994, 70, 176-82). Efficacy and non-selective MMP inhibitor BB94 ((2S, 3R) -5-methyl-3-{[(1S) -1- (methylcarbamoyl) -2-phenylethyl] carbamoyl} -2-[( 2-thienylthio) methyl] hexanohydroxyamic acid, batimastat, inhibits angiogenesis by inhibiting the invasion of endothelial cells of the lowermost membrane (G. Tarboletti, A. Garofalo, D Belotti, T. Drudis, P. Borsotti, E. Scanziani, PD Brown, R. Giavazzi, J. Natl. Cancer Inst., 1995, 87, 293-8). There is evidence that this method requires active MMP-2 and / or 9.

Thus, non-selective MMP inhibitors that inhibit MMP-1 and / or 2 and / or 9 are expected to impair wound healing. As described above, since MMP-14 is responsible for the activity of MMP-2, inhibition of MMP-14 can also cause impaired wound healing.

Production of MMP-3 has also been described in tissue damage and colon (SL Pender, SP Tickle, AJ Docherty, D. Howie, NC Wathen, TT MacDonald, J. Immunol., 1997, 158, 1582; CJ Bailey, RM Hembry, A. Alexander, MH Irving, ME Grant, CA Shuttleworth, J. Clin.Pathol., 1994, 47, 113-6) or duodenum (UK Saarialho-Kere, M. Vaalamo, P. Puolakkainen, K.). Airola, WC Parks, ML Karjalainen-Lindsberg, Am. J. Pathol., 1996, 148, 519-26]. MMP-1 and MMP-2 also appear to be needed during the healing phase of this condition. Selective MMP-3 inhibitors will be more effective than nonselective inhibitors.

MMP-3 can also be used to treat dermatological disorders, such as dystrophic bullous epidermolysis (T. Sato, K. Nomura, I. Hashimoto, Arch. Dermatol. Res., 1995, 287, 428) and herpes dermatitis ( K. Airola, M. Vaalamo, T. Reunala, UK Saarialho-Kere, J. Invest.Dermatology, 1995, 105, 184-9.

Rupture of atherosclerosis plaques with MMP-3 can lead to heart or cerebral infarction (F. Mach, et al., Circulation, 1997, 96, 396-9). Thus, MMP-3 inhibitors may be useful for treating embolism symptoms, such as those caused or exacerbated by chronic or acute heart or cerebral infarction.

MMP-12 (macrophage elastase) is believed to contribute to the pathology of atherosclerosis, gastrointestinal ulcers and emphysema. For example, in an atherosclerotic developmental rabbit model, MMP-12 is abundantly expressed by macrophage foam cells (S. Matsumoto, et al, Am. J. Pathol. 1998, 153, 109). MMP-12 is also abundantly expressed by macrophages in the vicinity of degenerating mucosal epithelium in human gastric ulcers, as found in patients with ulcerative colitis and Crohn's disease (M. Vaalamo, et al, Am j.Pathol., 1998, 152, 1005]). MMP-12 is believed to be important for the progression of lung injury by smoking. In a smoking-induced emphysema model, mice lacking the MMP-12 gene did not develop a condition, while wild-type mice suffered from apparent lung injury (RD Hautamaki, et al, Science, 1997, 277, 2002). ).

For a recent paper by MMP, see Zask et al, Current Pharmaceutical Design, 1996, 2, 624-661; Beckett, Exp. Opin. Ther. Patents, 1996, 6, 1305-1315; And Beckett et al, Drug Discovery Today, vol 1 (no. 1), 1996, 16-26.

Other names for the various MMPs and the substrates acting on them are shown in the table below (Zask et al., Supra).

enzyme Other designations Desirable substrate MMP-1 Collagenase-1, Interstitial Collagenase Collagen I, II, III, VII, X, Gelatin MMP-2 Gelatinase A, 72kDa Gelatinase Gelatin, collagen IV, V, VII, X, elastin, fibronectyl; Enabled Pro-MMP-13 MMP-3 Stromelysin-1 Proteoglykens, Lamini, Fibronectin, Gelatin MMP-7 Pump, matlyricin Proteoglycans, laminin, fibronectin, gelatin, collagen IV, elastin; Activates pro-MMP-1 and -2 MMP-8 Collagenase-2, neutrophil collagenase Collagen I, II, III MMP-9 Gelatinase B, 92kDa Gelatinase Gelatin, Collagen IV, V, Elastin MMP-12 Large cell metalloelasterase Activates elastin, collagen IV, fibronectin, pro-MMP-2 and -3 MMP-13 Collagenase-3 Collagen I, II, III, Gelatin MMP-14 MT-MMP-1 Activates pro-MMP-2 and -13, gelatin MMP-15 MT-MMP-2 Unknown MMP-16 MT-MMP-3 Enabled Pro-MMP-2 MMP-17 MT-MMP-4 Unknown

Many publications, including those described in the paper, describe chemical formulas as MMP inhibitors. Wherein "A" is known as the "alpha" group and XCO is a zinc bond group such as a carboxylic acid or hydroxyamic acid residue.

Beckt et al. Describe that a vast range of groups can be resistant at the P ₂ 'position without clearly affecting the behavior of the compound.

International patent applications WO96 / 33165 and WO96 / 33161 (British Biotech Pharmaceyticals Ltd.) include, in particular, P ₁ ', which may be substituted phenyl (C ₁ -C ₆ ) alkyl and P Compounds of the general formula “GENMMP” are generally disclosed wherein ₃ ′ is a CHR ^x R ^y group wherein R ^x and R ^y are a phenyl or heteroaryl ring which may be substituted. It has been described as being a selective inhibitor of MMP-3 and MMP-7 over anase (MMP-1) and 72KDa gelatinase (MMP-2).

International patent applications WO96 / 16027 (Syntex Inc. and Agouron Pharmaceuticals Inc.) include COX comprising CO ₂ H and CONHOH, with P ₁ 'substituted. R ² X group containing aryl (C _0-4 alkylene) which may be, and P ₃ ′ is (CH ₂ ) _p R ⁷ wherein 2p is from 0 to 4, provided that when p is not 0, R ² A compound of formula "GENMMP" as described above is disclosed wherein X is biphenylalkyl and R ⁷ is aryl or heteroaryl. Compounds in which p is 0,2 or 3 are preferred, and compounds in which p is 0 and COX is CO ₂ H or CONHOH are described as being preferred for matrilysin (ie, MMP-7) inhibition.

Numerous compounds of the formula "GENMMP" from WO 96/16027, for example X is OH, P ₁ 'is an optionally 4'-substituted biarylpropyl group, P ₂ ' is isobutyl, Compounds where P ₃ ′ is 4-methoxycarbonylphenyl are disclosed by the Aguroron Group (Second Meeting on Drug and Bioorganic Chemistry at Steamboat Springs, Colorado, January 1997). These compounds have been reported to be poor at mitigating MMP-3 / MMP-2 selectivity. It has been found that the use of alpha-substituents and the substitution of 4-methoxycarbonylphenyl residues with 4-methylthiophenyl groups greatly enhances MMP-3 / MMP-2 selectivity.

Beckett's (above) article also describes an agouron compound of formula "GENMMP" wherein X is OH, P ₁ 'is biphenylpropyl, P ₂ ' is t-butyl, and P ₃ 'is 4-pyridyl ( Paper # 31). Since these compounds have nearly identical K _i values for MMP-3 and MMP-2, MMP-3 is not selective over MMP-2.

International Patent Application WO95 / 12603 (Syntex) discloses a compound of formula "GENMMP" wherein P ₃ 'is a substituted phenyl moiety and P ₁ ' comprises arylalkyl, considered to be MMP-3 and MMP-7 inhibitors. It is starting.

We now have a good activity for MMP-3, MMP-12 and MMP-13, and the MMP inhibitor compounds having good selectivity for MMP-3 over other MMPs such as MMP-1, 2, 9 and 14 I got to know the military. It has been found that MMP-3 selectivity for this group of compounds is markedly dependent on the particular combination of P ₁ 'and P ₃ ' substituents, which is an unpredictable effect from the techniques described above.

Thus, according to the invention, there are provided compounds of formula I and pharmaceutically acceptable salts thereof.

Where

R ¹ is H, OH, C _1-4 alkyl, C _1-4 alkoxy or C _2-4 alkenyl,

R ² is fluoro, indolyl, imidazolyl, SO ₂ (C _1-4 alkyl), C _5-7 cycloalkyl, or OH, SH, CONH ₂ , CO ₂ H, NH ₂ or NHC which may be protected C _1-6 alkyl which may be substituted by (= NH) NH ₂ groups, C _5-7 cycloalkyl which may be substituted by C _1-6 alkyl, or OH, C _1-6 alkoxy, which may be protected, Benzyl which may be substituted by benzyloxy or benzylthio,

Any protecting group for the OH, SH, CONH ₂ , NH ₂ or NHC (= NH) NH ₂ group is selected from C _1-6 alkyl, benzyl, C _1-6 alkanoyl, and for any of the CO ₂ H The protecting group is selected from C _1-6 alkyl or benzyl,

R ³ , R ⁵ and R ⁶ are each independently selected from H and F,

R ⁴ is CH ₃ , Cl or F,

X is HO or HONH,

Y is direct bond or 0,

Z is a group of formula a or formula b,

[Wherein R ¹⁰ is C _1-4 alkyl, C _1-4 alkoxymethyl, hydroxy (C _2-4 alkyl), carboxy (C _2-4 alkyl) or (amino or dimethylamino) C _2-4 alkyl ,

R ¹¹ is phenyl, naphthyl or pyridyl, which may be substituted by up to 3 substituents independently selected from halo and methyl,

R ¹⁴ is H, OH, CH ₃ or halo]

Ar is a group of the formula c, d or e.

[Wherein A is N or CR ¹² ,

B is N or CR ¹³ ,

Provided that both A and B are not N at the same time,

R ⁷ and R ⁹ are each independently H or F,

R ⁸ , R ¹² and R ¹³ are H, CN, C _1-6 alkyl, hydroxy (C _1-6 alkyl), hydroxy (C _1-6 alkyl) alkoxy, C _1-6 alkoxy (C _1-6 Alkoxy, (amino or dimethylamino) C _1-6 alkyl, CONH ₂ , OH, halo, C _1-6 alkoxy, (C _1-6 alkoxy) methyl, piperazinylcarbonyl, piperidinyl, C (NH ₂ ) = NOH or C (= NH) = NHOH, provided that at least two of R ⁸ , R ¹² and R ¹³ are H;

"Alkyl" groups and "alkenyl" groups, including alkyl moieties of "alkoxy" groups, may be branched or straight if carbon number permits.

"Halo" means F, Cl, Br or I.

The compounds of the present invention are MMP inhibitors, and in particular, are potent and selective MMP-3 inhibitors with good selectivity over MMP-1,2,9 and / or 14. In addition, certain compounds of the invention have useful MMP-12 and / or 13 inhibitory activity.

Preferably, R ¹ is H, OH, C _1-4 alkyl or C _1-4 alkoxy.

More preferably, R ¹ is H, OH, n-propyl or ethoxy.

Most preferably, R ¹ is H.

Preferably R ² is C _1-6 alkyl, C _1- which may be substituted by indolyl, C _1-6 alkylthio, SO ₂ (C _1-4 alkyl), C _5-7 cycloalkyl, OH or SH C _5-7 cycloalkyl or benzyl, which may be substituted by ₆ alkyl.

More preferably, R ² is cyclohexyl which may be substituted by C _1-6 alkyl, C _1-6 alkyl which may be substituted by OH, SO ₂ (C _1-4 alkyl) or C _5-7 cycloalkyl Or benzyl.

However, more preferably, R ² is cyclohexylmethyl, isopropyl, 1-methylcyclohexyl, t-butyl, C (CH ₃ ) ₂ SO ₂ CH ₃ , benzyl or C (CH ₃ ) ₂ OH.

But more preferably R ² is isopropyl, t-butyl or benzyl.

Most preferably R ² is t-butyl.

Preferably, Z is of formula a, [Wherein R ¹⁰ is C _1-4 alkyl, C _1-4 alkoxymethyl or hydroxy (C _2-4 alkyl) and R ¹¹ may be substituted with up to 3 substituents independently selected from halo and methyl Phenyl or pyridyl], or to be.

More preferably Z is represented by the formula a, Wherein R ¹⁰ is C _1-4 alkyl, C _1-4 alkoxymethyl or hydroxy (C _2-4 alkyl) and R ¹¹ is phenyl, pyridin-4-yl or pyridin-3-yl , or to be.

More preferably, however, Z is represented by the formula a, Wherein R ¹⁰ is CH ₃ , CH ₂ 0CH ₃ or CH ₂ OH, and R ¹¹ is phenyl, pyridin-4-yl or pyridin-3-yl; or to be.

Most preferably, Z is to be.

Preferably R ³ is H.

Preferably R ⁴ is F when Y is O.

Preferably R ⁴ is Cl or CH ₃ when Y is a direct bond.

Preferably R ⁵ is H.

Preferably R ⁶ is H.

Preferably Ar is a group of formula c.

<Formula c>

Where

A is CR ¹² and B is CR ¹³

R ⁷ and R ⁹ are each independently H or F,

R ⁸ and R ¹³ are each independently H, F, Cl, CN, CONH ₂ , CH ₃ or OCH ₃ ,

R ¹² is H, C _1-6 alkyl, CN, hydroxy (C _2-6 alkyl), (amino or dimethylamino) C _2-6 alkyl, CONH ₂ , OH, halo, C _1-6 alkoxy, (C _1-6 alkoxy) methyl, piperazinylcarbonyl, piperidinyl, C (NH ₂ ) = NOH or C (= NH) = NHOH.

More preferably Ar is a group of formula c.

<Formula c>

A is CR ¹² , B is CR ¹³ , and R ⁷ , R ⁸ and R ⁹ are H.

More preferably, however, Ar is a group of formula (c).

<Formula c>

A is CR ¹² , B is CR ¹³ , R ⁷ , R ⁸ and R ⁹ are H,

R ¹² is H, C _1-6 alkyl, CN, hydroxy (C _2-6 alkyl), (amino or dimethylamino) C _2-6 alkyl, CONH ₂ , OH, halo, C _1-6 alkoxy, (C _1-6 alkoxy) methyl, C (NH ₂ ) = NOH or C (= NH) = NHOH,

R ¹³ is H, OCH ₃ , CN, CONH ₂ , CH ₃ or F.

But more preferably Ar is phenyl, 3-methoxyphenyl, 4-cyanophenyl, 3-cyanophenyl, 3-carbamoylphenyl or 4-hydroxyamidinophenyl.

Most preferably Ar is phenyl or 3-methoxyphenyl.

Preferred groups of materials are compounds in which the substituents have the values described in the examples and salts thereof.

That is, R ¹ is H, OH, n-propyl or ethoxy,

R ² is t-butyl, isopropyl or benzyl,

Z is a chemical formula Wherein R ¹⁰ is CH ₃ , CH ₂ 0CH ₃ or CH ₂ OH, and R ¹¹ is phenyl, pyridin-4-yl or pyridin-3-yl; or ego,

R ³ is H,

R ⁴ is CH ₃ , Cl or F,

R ⁵ is H,

R ⁵ is H,

Ar is phenyl, 3-methoxyphenyl, 4-cyanophenyl, 3-cyanophenyl, 3-carbamoylphenyl or 4-hydroxyamidinophenyl.

Another preferred group is the compounds of the following examples and salts thereof.

Most preferred materials are those selected from the following examples 3, 4, 8, 14,15, 16, 22, 29, 30, 31 and 32, and the salts thereof.

Pharmaceutically acceptable salts are well known to those skilled in the art and include, for example, those mentioned in the techniques described above, and are described in Berge et al, J. Pharm. Sci., 66, 1-19 (1977). Suitable acid addition salts are formed from acids which form non-toxic salts, and are composed of hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, hydrogen sulfate, phosphate, hydrophosphate, acetate, trifluoroacetic acid, gluconate. Acid salts, lactates, salicylates, citrates, tartarates, ascorbates, succinates, maleates, fumarates, gluconates, formates, benzoates, methanesulfonates, ethanesulfonates, benzenesulfonates and p-toluenesulfonic acids Salts.

Pharmaceutically acceptable base addition salts are well known to those skilled in the art and include, for example, those mentioned in the techniques described above, and are formed from bases which form non-toxic salts, and include aluminum, calcium, lithium, magnesium, potassium, sodium And salts of non-toxic amines such as zinc salts and diethanolamines.

Certain compounds of formula (I) may exist as geometric isomers. Compounds of formula (I) may exist in two or more stereoisomeric forms because they may have one or more asymmetric centers apart from a particular center of formula (I). The present invention includes all individual stereoisomers and geometric isomers of the compounds of formula (I) comprising the Z group, apart from the specific center of formula (I), and mixtures thereof.

Another aspect of the invention is a pharmaceutical composition comprising a compound or salt according to the above definition and a pharmaceutically acceptable adjuvant, diluent or carrier.

Yet another aspect of the present invention is a compound or salt used as a medicament according to the above definition.

Another aspect of the invention is the above definition in the manufacture of a medicament for treating a condition mediated by one or more matrix metalloproteases, in particular MMP-3 and / or MMP-12 and / or MMP-13. It is to use the compound and salt according to

Yet another aspect of the invention is a method of treating a condition mediated by one or more matrix metalloproteases, in particular MMP-3 and / or MMP-12 and / or MMP-13.

It will be appreciated that treatment includes alleviation as well as prevention of confirmed symptoms of MMP-mediated conditions.

The invention also provides a process for the preparation of the compounds of the invention as described below and in the Examples below. Those skilled in the art will appreciate that compounds of the present invention may be prepared by methods other than those described in detail herein, by variations of the methods described below and / or by methods known in the art, and variations thereof. Suitable guidance on synthesis, functional group modifications, the use of protecting groups, and the like is described, for example, in "Comprehensive Organic Transformations" by RC Larock, VCH Publishers Inc. (1989), "Advanced Organic Chemistry" by J March, Wiley Interscience (1985), "Designing Organic Synthesis" by S Warren, Wiley Interscience (1978), "Organic Synthesis-The Disconnection Approach" by S Warren, Wiley Interscience (1982 ), "Guidebook to Organic Synthesis" by RK Mackie and DM Smith, Longman (1982), "Protective Groups in Organic Synthesis" by TW Greene and PGM Wuts, John Wiley and Sons Inc. (1991), and PJ Kocienski, in "Protecting Groups", Georg Thieme Verlag (1994).

In the following methods, unless defined otherwise, substituents are as defined above for the compounds of formula (I) above.

<Method 1>

Compounds of formula (I), wherein X is OH, can be obtained through the corresponding compounds of formula (II), in which X ₁ can be modified to a carboxy group under conditions that do not result in substantial modification of other parts of compound II. Suitable examples of such groups are CO ₂ (t-butyl or methyl). The t-butyl group can be decomposed by reaction with an acid such as hydrogen chloride or trifluoroacetic acid (TFA) in a suitable solvent such as anhydrous dichloromethane or dioxane under suitable temperatures such as 0 ° C. to 20 ° C. The methyl ester can be hydrolyzed with a hydroxide, such as lithium hydroxide, in a suitable solvent system, such as a mixture of tetrahydrofuran / water at room temperature.

Compounds of formula (II) are known in the art and can be prepared by the methods illustrated in the following preparations, for example by coupling suitable amine and acid derivatives which may be provided by known chemistry.

<Method 2>

Treatment of a compound of formula (I), wherein X is OH with hydroxylamine, results in suitable solvents such as N, N-dimethylformamide (DMF) and N-[(dimethylamino ) -1H-1,2,3-triazole [4,5-b] pyridin-1-ylmethylene] -N-methylmethanium hexafluorophosphate N-oxide ("HATU", Tet. Letts (1994) 35, 2279) from the generation of hydroxylamine salts (e.g. hydrochloride) with suitable bases such as tertiary amines (e.g. diisopropylethylamine) in a coupling agent. From the corresponding compound of formula (I) wherein X is OH, compounds of formula (I) wherein X is NHOH can be obtained.

Compounds of formula I wherein X is OH can be prepared by conventional methods and by the methods described herein.

<Method 3>

Treating a compound of formula (I) wherein X is OH with O-allylhydroxyamine, for example, a suitable solvent such as N, N-dimethylformamide (DMF) or dichloromethane at a suitable temperature, such as 0 ° C. to 20 ° C. and Coupling agents, for example tertiary amines (eg, diisopropylethyl) in peptide coupling agents such as 7-azabenzotriazol-1-yloxytris (pyrrolidino) phosphonium hexafluorophosphate ("PyAOP") Generation from O-allylhydroxyamine salts (e.g. hydrochloride) with a suitable base such as amine) gives a compound of formula I wherein X is NHOH from the corresponding compound of formula I wherein X is OH . This step provides a compound of formula III.

Such coupling methods are generally described in Tet. Letts. (1994) 35, 2279.

The compound of formula III is treated with ammonium formate in the presence of a suitable catalyst such as bis (triphenylphosphine) palladium (II) acetate in a suitable solvent such as aqueous ethanol under a suitable temperature such as the reflux temperature of aqueous ethanol, whereby X is And a compound of formula I, which is NHOH.

<Method 4>

Compounds of formula (I), wherein X is NHOH and R ¹ is OH, react the compound of formula (IV) with hydroxylamine, for example hydroxyl in a suitable base such as sodium methoxide and hydrochloride in a suitable solvent such as methanol It can manufacture by generation from an amine salt.

Compounds of formula (VI) can be prepared by conventional methods as exemplified in the preparations below.

<Method 5>

Compounds of formula (I) can be prepared from compounds of formula (V) by cross-coupling with compounds of formula (VI).

Wherein X ₂ is a protected acid such as t-butyl or methyl ester group and LG is a cross-coupling leaving group such as I, Br or OSO ₂ CF ₃ . The cross-coupling reaction is carried out with bis (tri-o-tolyl) phosphine palladium (II) acetate with a suitable base such as triethylamine in a suitable solvent such as acetonitrile or DMF at a suitable temperature such as 50 ° C. to 150 ° C. It can be carried out in the presence of the same catalyst.

This type of reaction is generally described by Heck Tet. Letts. (1984) 25, 2271 and numerous other documents.

Compounds of formula (V) can be prepared by conventional methods such as modifications as described in the preparations below.

Compounds of formula (VI) can be prepared by conventional methods such as those described in the following preparations and by Synthesis (1984) 709; J. Chem Soc Perkin Trans I (1977) 1841; J Org Chem (1994) 59, 6095; Supra, (1979) 44, 4444 and Tet. Letts. (1997) 38, 1749, the disclosure of which is incorporated herein by reference.

The product obtained from this reaction is a mixture of compounds of formula (VIIa) and VIIB, wherein X ₂ is defined for compounds of formula (V) above.

The compounds of formulas (VIIa) and (VIIb) are reacted with diimides, which may be generated from, for example, p-toluenesulfonyl hydrazide, or protected, using conventional methods such as hydrogenation in the presence of a catalyst. The deprotected acid residue X ₂ can be transformed into a compound of formula I wherein X is OH.

Other protective methods during the synthesis of the compounds of the present invention which can be achieved by conventional techniques, for example by the conventional methods described in the above Green and Wuts and Kocienski's literature. And the accompanying deprotection methods will be apparent to those skilled in the art.

If desired or necessary, the compound of formula (I) is converted into a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable salts of the compounds of formula (I) are usually prepared appropriately by mixing together a solution of the compound of formula (I) with the desired acid or base. Such salts may be precipitated out of solution and collected by filtration or may be collected by other means such as evaporation of the solvent.

Certain compounds of the invention can be interconverted to other specific compounds of the invention by methods well known from the literature.

The compounds of the present invention may be provided by methods described in the methods and examples herein, or by suitable modifications thereof using methods known in the art. It should be understood that the synthetic conversion methods described herein can be performed in a variety of different orders to enable effective synthesis of the desired compounds. Skilled chemists will use their judgment and techniques for the most effective sequence for the synthesis of a given target compound.

Compounds and salts of the present invention will be separated and purified by conventional methods.

Separation of diastereoisomers can be accomplished by conventional techniques, for example by fractional crystallization of a stereoisomer mixture of a compound of formula (I) or a suitable salt or derivative thereof, chromatography or H.P.L.C. Each enantiomer of the compound of formula (I) is separated from the corresponding optically pure intermediate or by a splitting method such as HPLC of the corresponding racemate using a suitable chiral support, or with an acid or base which is optically active as appropriate with the corresponding racemate. It can also be prepared by fractional crystallization of diastereomeric salts formed by the reaction of.

When used in humans, the compounds of formula (I) or salts thereof may be administered alone, but will generally be administered in a mixture with a pharmaceutically acceptable diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, sublingual administration in the form of tablets containing excipients such as starch or lactose, or capsules or turbulences alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavoring or coloring agents. Can be administered orally. The compounds or salts may be incorporated into capsules or tablets that target the colon or duodenum, which delay the degradation of the capsules or tablets for a certain time after oral administration. Degradation can be controlled by the sensitivity of the agent to bacteria in the duodenum or colon, so that no substantial degradation occurs before reaching the target area of the gastrointestinal tract. The compounds or salts may be injected parenterally, eg intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of sterile aqueous solutions or suspensions which may contain enough salt or other substances such as glucose to make the solution isotonic with the blood. They may be administered topically in the form of sterile creams, gels, suspensions, lotions, ointments, powdered powders, sprays, drug-incorporated dressings or skin patches. For example, they may be incorporated into a cream consisting of an aqueous or oily emulsion of polyethylene glycol or liquid paraffin, or they may also be incorporated into an ointment consisting of a white wax soft paraffin base, or a cellulose or polyacrylate derivative or other viscosity modifier. As a hydrogel with, or as a dry powder or liquid spray or an aerosol with butane / propane, HFA or CFC propellant, or as a drug-incorporated dressing or tool dressing, a white soft paraffin or polyethylene glycol immersion gauge dressing or It may be incorporated with hydrogels, hydrocolloids, alginates or film dressings. The present compounds and salts may also be administered eye to eye with suitable buffers, viscosity modifiers (eg cellulose derivatives), preservatives (eg benzalkonium chloride (BZK)) and tone control agents (eg sodium chloride) as eye drops. Such formulation techniques are well known in the art.

All such formulations may also include suitable stabilizers and preservatives.

For oral and parenteral administration to human patients, the daily dosage level of the compound of formula (I) or salt thereof is about 0.001 to 20, preferably 0.01 to 20, more preferably 0.1 to 10, and most preferably 0.5 to 5 mg. / kg (single or divided dose). Thus tablets or capsules of the present compounds will suitably contain 0.1 to 500, preferably 50 to 200 mg of the active compound for one or two or more administrations.

For topical administration to human patients with chronic lesions, the daily dosage level of the compound may be from 0.01 to 50 mg / ml, preferably 0.3 to 30 mg / ml, in suspension or other formulation.

In any case, doctors will determine the actual dosage that is best suited for each patient, which varies with the age, weight and response of the particular patient. The dosage is an example of an average, and of course higher or lower dosage ranges are, of course, in each case and are within the scope of the present invention.

<Test method>

The ability of the present compounds to inhibit hemoglobin peptide degradation by MMPs 1, 2, 3, 9, 12, 13 and 14 is described below.

Assays for MMP 2, 3, 9, and 14 are described in Knight et al. Fed. Euro. Biochem. Soc., 296 (3), 263-266; 1992 is based on a slight modification of the original protocol as described below.

<Inhibition of MMP-1>

(i) enzyme preparation

Catalytic domain MMP-1 was prepared by Pfizer Central Research. Aminophenylmercuric acetate (APMA) was added at a final concentration of 1 mM at 37 ° C. for 20 minutes to activate the stock solution of MMP-1 (1 μM). MMP-1 was then diluted to a concentration of 10 nM with Tris-HCl assay buffer (50 mM Tris, 200 mM NaCl, 5 mM CaCl ₂ , 20 μM ZnSO ₄ , 0.05% Brij 35, pH 7.5). The final concentration of enzyme used in the assay was 1 nM.

(ii) substrate

The fluorophore substrate used in the assay is described by Bickett et al, Anal. Biochem, 212, 58-64, 1993], Dnp-Pro-β-cyclohexyl-Ala-Gly-Cys (Me) -His-Ala-Lys (N-Me-Ala) -NH2. . The final substrate concentration used in the analysis was 10 nM.

(iii) determination of enzyme inhibition

The test compound was dissolved in dimethyl sulfoxide and diluted with assay buffer so that up to 1% of dimethyl sulfoxide was present. Test compounds and enzymes were added to each well of a 96 well plate and allowed to equilibrate in an orbital shaker at 37 ° C. for 15 minutes before the substrate was added. The plates were then incubated at 37 ° C. for 1 hour and then fluorescence (substrate) using a fluorometer (Fluorostar from Ilesbury BMG Lab Technologies, UK) at an excitation wavelength of 355 nm and an emission wavelength of 440 nm. Degradation). The potency of the inhibitor was determined from the amount of substrate degradation obtained using a range of test compound concentrations and the IC ₅₀ value (the concentration of inhibitor required to inhibit 50% enzyme activity) was calculated from the obtained dose-response curve.

<Inhibition of MMP-2, MMP-3 and MMP-9>

(i) enzyme preparation

Catalytic domains MMP-2, MMP-3 and MMP-9 were prepared by Pfizer Central Research. Aminophenylmercuric acetate (APMA) was added at a final concentration of 1 mM to activate stock solutions (1 μM) of MMP-2, MMP-3 and MMP-9. APMA at a final concentration of 1 mM was added to MMP-2 and MMP-9 and incubated at 37 ° C. for 1 hour. MMP-3 was activated by the addition of 2 mM APMA and incubated at 37 ° C. for 3 hours. The enzyme was then diluted with Tris-HCl assay buffer (100 mM Tris, 100 mM NaCl, 10 mM CaCl ₂ and 0.16% Brij 35, pH 7.5) to a concentration of 10 nM. The final concentration of enzyme used in the assay was 1 nM.

(ii) substrate

The fluorophore substrate used in this screen is described in Nagase et al, J. Biol. Chem., 269 (33), 20952-20957, 1994) Mca-Arg-Pro-Lys-Pro-Tyr-Ala-Nva-Trp-Met-Lys (Dnp) -NH ₂ (Bachem Ltd, Essex, UK). These substrates were chosen because they have balanced hydrolysis rates (k _cat / k _m of 54,000, 59,400 and 55,300 s ⁻¹ M ⁻¹ , respectively) for MMP 2, 3 and 9. The final substrate concentration used in the assay was 5 μΜ.

(iii) determination of enzyme inhibition

The test compound was dissolved in dimethyl sulfoxide and diluted with test buffer solution (as above) to ensure that up to 1% of dimethyl sulfoxide was present. Test compounds and enzymes were added to each well of a 96 well plate and allowed to equilibrate in an orbital shaker at 37 ° C. for 15 minutes before adding to the substrate. The plates were then incubated for 1 hour at 37 ° C. and then fluorescence (substrate degradation) was determined using a fluorometer (Fluorostar of Islesbury BMG Labs, UK) at an excitation wavelength of 328 nm and an emission wavelength of 393 nm. The potency of the inhibitor was determined from the amount of substrate degradation obtained using a range of test compound concentrations and the IC ₅₀ value (the concentration of inhibitor required to inhibit 50% enzyme activity) was calculated from the obtained dose-response curve.

<Inhibition of MMP-12 (human macrophage elastase)>

(i) enzyme preparation

Catalytic domain MMP-12 (200 μg / ml) was used. MMP-12 was then diluted to 240 ng / ml with Tris-HCl assay buffer (50 mM Tris, 200 mM NaCl, 5 mM CaCl ₂ , 20 μM ZnSO ₄ , 0.02% Brij 35) at pH 7.4. The final concentration of enzyme used in the assay was 60 ng / ml.

(ii) substrate

The fluorophore substrate used in this assay was DNP-Pro-Cha-Gly-Cys (Me) -His-Ala-Lys (NMA) -NH ₂ . The final substrate concentration used in the assay was 10 μΜ.

(iii) determination of enzyme inhibition

Test compounds were dissolved in dimethyl sulfoxide and diluted with assay buffer so that up to 1% of dimethyl sulfoxide was present. Test compounds and enzymes were added to each well of a 96 well plate and allowed to equilibrate in an orbital shaker for 15 minutes at room temperature before the substrate was added. The plates were then incubated at room temperature for 2 hours and then fluorescence (substrate degradation) was determined using a fluorometer at excitation wavelength 360 nm and emission wavelength 460 nm. The potency of the inhibitor was determined from the amount of substrate degradation obtained using a range of test compound concentrations and the IC ₅₀ value (the concentration of inhibitor required to inhibit 50% enzyme activity) was calculated from the obtained dose-response curve.

<Inhibition of MMP-13>

(i) enzyme preparation

Human recombinant MMP-13 was prepared in Pan Vera Corporztion (Madison, Wisconsin) and characterized in Pfizer (Groton, Connecticut). 1.9 mg / ml of the stock solution was activated with 2 mM APMA for 2 hours at 37 ° C. MMP-13 was then diluted to 5.3 nM with assay buffer of pH 7.5 (50 mM Tris, 200 mM NaCl, 5 mM CaCl ₂ , 20 μM ZnSO ₄ and 0.02% Brij 35). The final concentration of enzyme used in the assay was 1.3 nM.

(ii) substrate

The fluorophore substrate used in this screen was Dnp-Pro-Cha-Gly-Cys (Me) -His-Ala-Lys (NMA) -NH ₂ . The final substrate concentration used in the assay was 10 μΜ.

(iii) determination of enzyme inhibition

The test compound was dissolved in dimethyl sulfoxide and diluted with assay buffer so that up to 1% of dimethyl sulfoxide was present. Test compounds and enzymes were added to 96 well plates. The reaction was initiated by adding a substrate to each well. Fluorescence intensity using a fluorometer (Cytofluor II of PerSeptive Biosystems, Inc., Framingham, Mass.) At excitation wavelength 360 nm and emission wavelength 460 nm on a 96 well plate Was determined. The potency of the inhibitor was determined from the amount of substrate degradation obtained using a range of test compound concentrations and the IC ₅₀ value (the concentration of inhibitor required to inhibit 50% enzyme activity) was calculated from the obtained dose-response curve.

<Inhibition of MMP-14>

(i) enzyme preparation

The catalytic domain MMP-14 was purchased from Professor Tschesche of the Department of Biochemistry, Faculty of Chemistry, University of Bielefeld, Germany. 10 μM of stock solution was activated for 20 min at 25 ° C. and 5 μg / ml of trypsin (Sigma, Dorset, UK) was added. 50 μg / ml of soy trypsin inhibitor (Sigma, Dorset, UK) was then added to neutralize trypsin activity, and the enzyme stock was then tris-HCl assay buffer (100 mM Tris, 100 mM NaCl, 10 mM CaCl ₂ and 0.16%). Brij 35, pH 7.5). The final concentration of enzyme used in the assay was 1 nM.

(ii) substrate

The fluorophore substrate used in this screen is described by Will et al, J. Biol. Chem., 271 (29), 17119-17123, 1996; Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH ₂ (Bachem Ltd, Essex, UK). The final substrate concentration used in the assay was 10 μΜ.

Enzyme inhibition by test compounds was also determined as described for MMPs 2, 3 and 9.

Some activity data for certain compounds of the examples are shown in the table below.

The compounds of Examples 6, 8, 9, 14, 15 and 22 have MMP-3 IC ₅₀ values ranging from 8 to 65 nM and MMP-3 / MMP-2 selectivity between 195 and 930.

<Examples and Production Examples>

Melting points were determined using open glass capillary and Galenkamp melting point apparatus and were not corrected. Obtain nuclear magnetic resonance (NMR) data using Varian Unity Inova-400, Varian Unity Inova-300, or Bruker AC300 spectrometer, in ppm from tetramethylsilane Cited. Finnigan mat with mass spectrometry (MS) data. (Finnigan Mat.) Obtained on TSQ 7000 or Fisons Instruments Trio 1000. Ion calculations and actual measurements quoted relate to the lowest mass isotope composition. Infrared (IR) spectra were measured using a Nicolet Magna 550 Fourier modified infrared spectrometer. Flash chromatography relates to column chromatography on silica gel (Kieselgel 60, 230-400 mesh of E. Merck, Darmstadt). E. Merck's Kigelgel 60 F ₂₅₄ plate was used for TLC and compounds were visualized using UV light, 5% aqueous potassium permanganate or a reagent from Dragendorff (sprayed with aqueous sodium nitrite). Hexane refers to a mixture of hexanes (hplx grade) at bp 65 to 70 ° C. Ether means diethyl ethyr. Acetic acid means glacial acetic acid. 1-hydroxy-7-aza-1H-1,2,3-benzotriazole (HOAt), N-[(dimethylamino) -1H-1,2,3-triazolo [4,5-b] pyridine -1-ylmethylene] -N-methylmethanium hexafluorophosphate N-oxide (HATU) and 7-azabenzotriazol-1-yloxytris (pyrrolidino) phosphonium hexafluorophosphate (PyAOP) Perceptive Biosystems Yu. K. It was purchased from PerSeptive Biosystems UK Ltd. "DIPE" means diisopropyl ether. Reversed phase silica gel for flash chromatography was obtained from Fluka (Fluka 100, C18, 40-63 μ). Pentane means hplc grade n-pentane (bp 35-37 ° C.).

Note: Certain derivatives of 4-aminobiphenyl are described in the preparation below. 4-aminobiphenyl is known to be a human carcinogen. Similar substances should therefore be handled with care. See, for example, Yuta, K., Jurs, P.C., J. Med. Chem. (1981), 24 (3), 241-51; You, Z., Brezzell, M. D., Das, S. K., Hooberman, B. H., Shinsheimer, J. E. Mutat. Res. (1994), 320 (1-2), 45-58; Hecht, S. S., et al, J. Med. Chem. (1979), 22 (8), 981-7.

<Example 1>

(3R) -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl] amino} carbonyl) -6-[( 3-Methyl-4-phenyl) phenyl] hexanoic acid

Tert-butyl (3R) -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} in 20 ml nitrogen anhydrous dichloromethane) Trifluoroacetic acid (5) in a stirred solution of carbonyl) propyl] amino} carbonyl) -6- [3-methyl- (4-phenyl) phenyl] hexanoate (Preparation Example 3) (285 mg, 0.47 mmol) ml) was added dropwise over 5 minutes. This solution was stirred for 4 hours and concentrated under reduced pressure. The residue was dissolved in toluene, concentrated under reduced pressure (twice) and triturated with ether to give a colorless solid (210 mg, 82%).

m.p. 160-162 ° C (from ethyl acetate)

R _f 0.17 (hexane / ether / acetic acid = 50: 50: 1)

HPLC retention time 7.3 minutes (eluted with Phenomenex Magellen C ₁₈ silanated silica gel (5 μ), acetonitrile / water / trifluoroacetic acid = 70: 30: 0.1 (1 ml / min) , detected by uv (220 nm)

Elemental Analysis of C ₃₄ H ₄₂ N ₂ O ₄

Found: C, 75.22; H, 7.73; N, 5.16;

Theoretical value: C, 75.25; H, 7.80; N, 5.16%

<Example 2>

(2R) -2- {3- [3-chloro- (4-phenyl) phenyl] propyl} -N1-[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl ] Amino} carbonyl) propyl]-(N4-hydroxy) butanediamide

a) (3R) -6-[(3-chloro-4-phenyl) phenyl] -3-({[(1S) -2,2-dimethyl-1- in anhydrous dichloromethane (1 ml) at 0 ° C. nitrogen. ({[(1R) -1-phenylethyl] amino} carbonyl) propyl] amino} carbonyl) hexanoic acid (Preparation 4) (66 mg, 0.117 mmol) with diisopropylethylamine (78 μL, 0.456 mmol To the stirred solution of) was added O-allylhydroxylamine hydrochloride (17 mg, 0.152 mmol). 7-Azabenzotriazol-1-yloxytris (pyrrolidino) phosphonium hexafluorophosphate (79 mg, 0.152 mmol) was added in one portion and the mixture was stirred at 0 ° C. for 2 hours and then allowed to come to room temperature. Warmed. After one more hour, the mixture was poured into ethyl acetate (25 ml) and washed sequentially with 5% aqueous citric acid (2 × 10 ml) and saturated aqueous sodium hydrogen carbonate (2 × 10 ml). The organic solution was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The solid residue is suspended in ether (3 ml) and filtered to give (2R) -2- {3- [3-chloro- (4-phenyl) phenyl] propyl} -N1-[(1S) -2,2-dimethyl -1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl]-(N4-3-propenyloxy) butanediamide (58 mg, 82%) was obtained as a white solid.

b) (2R) -2- {3- [3-chloro- (4-phenyl) phenyl] propyl} -N1-[(1S) -2,2-dimethyl in ethanol / water (4: 1, 4 ml) -1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl]-(N4-3-propenyloxy) butanediamide (56 mg, 0.091 mmol) and ammonium formate (59 mg, 0.93 mmol) of the stirred mixture was heated to reflux under nitrogen to obtain a colorless solution. Bis (triphenylphosphine) palladium acetate (3.4 mg, 0.00465 mmol) was added and the mixture was heated at reflux for 40 minutes. After cooling, the brown solution was diluted with ethyl acetate (25 ml), washed with saturated aqueous sodium chloride (2 × 10 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (C ₁₈ silanated silica gel (40-63 μ), eluting with methanol: water = 5: 1) (2R) -2- {3- [3-chloro- (4- Phenyl) phenyl] propyl} -N1-[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl]-(N4-hydroxy) butanedia Mid (46 mg, 88%) was obtained as a colorless solid.

m.p. 107-109 ℃

R _f 0.43 (C ₁₈ silanized silica gel, methanol: water = 5: 1)

Elemental analysis for _{C 33 H 40 ClN 3 O 4} · 0.5H 2 O

Found: C, 67.69; H, 6. 90; N, 7.19;

Theoretical value: C, 67.51; H, 7.04; N, 7.16%

<Example 3>

N1-[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl]-(N4-hydroxy)-(2R) -2- {3 -[3-methyl- (4-phenyl) phenyl] propyl} butanediamide

a) (3R) -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} in anhydrous dimethylformamide (25 ml) at 0 ° C. nitrogen). Carbonyl) propyl] amino} carbonyl) -6-[(3-methyl-4-phenyl) phenyl] -hexanoic acid (Example 1) (974 mg, 1.79 mmol) and diisopropylethylamine (1.56 ml, 8.97 mmol) was added O-allylhydroxylamine hydrochloride (295 mg, 2.69 mmol). 7-Azabenzotriazol-1-yloxytris (pyrrolidino) phosphonium hexafluorophosphate (1.40 mg, 2.69 mmol) was added in one portion and the mixture was allowed to warm to room temperature. After 4.25 hours more, the mixture was poured into ethyl acetate (500 ml) and washed with saturated aqueous sodium hydrogen carbonate (2 × 200 ml). The aqueous wash was extracted with ethyl acetate (2 x 100 ml). The combined organic solution was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The solid residue is suspended in ether (3 ml), filtered and recrystallized from ethyl acetate to give N1-[(1S-2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl ) Propyl]-(2R) -2- {3- [3-methyl- (4-phenyl) phenyl] propyl}-(N4-3-propenyloxy) butanediamide (640 mg, 60%) in white Obtained as a solid.

R _f 0.31 (ethyl acetate / hexane = 1: 1)

b) N1-[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl]-(in ethanol / water (4: 1, 25 ml) 2R) -2- {3- [3-methyl- (4-phenyl) phenyl] propyl}-(N4-3-propenyloxy) butanediamide (794 mg, 1.32 mmol) and ammonium formate (419 mg , 6.64 mmol) was heated to reflux under nitrogen to obtain a colorless solution. Bis (triphenylphosphine) palladium acetate (40 mg, 0.066 mmol) was added and the mixture was heated at reflux for 90 minutes. After cooling, the brown solution was diluted with ethyl acetate (250 mg), washed with saturated aqueous sodium chloride (2 × 10 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (C ₁₈ silanated silica gel, eluting with methanol / water = 5: 1) and then triturated with methanol / diisopropyl ether to give N1-[(1S) -2,2-dimethyl- 1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl]-(N4-hydroxy)-(2R) -2- {3- [3-methyl- (4-phenyl) phenyl] Propyl} butanediamide (440 mg, 59%) was obtained as a colorless solid.

m.p. 114-116.5 ℃

R _f 0.23 (C ₁₈ silanated silica gel, methanol: water = 5: 1)

Elemental analysis for _{C 33 H 43 N 3 O 4} · 0.25H 2 O

Found: C, 72.60; H, 8.02; N, 7.31;

Theoretical value: C, 72.63; H, 7.80; N, 7.47%

<Example 4>

N1-[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl]-(2R) -2- [3- (3-fluoro- 4-phenoxyphenyl) propyl]-(N4-hydroxy) butanediamide

(3R) -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl in anhydrous dimethylformamide (10 ml) at 0 ° C. nitrogen) ) Propyl] amino} carbonyl) -6- (3-fluoro-4-phenoxyphenyl) hexanoic acid (Preparation 5) (731 mg, 1.30 mmol) and diisopropylethylamine (220 μl, 1.30 mmol) To a stirred solution of N-[(dimethylamino) -1H-1,2,3-triazolo [4,5-b] pyridin-1-ylmethylene] -N-methylmethanium hexafluorophosphate N-oxide (740 mg, 1.95 mmol) was added. After 25 minutes, hydroxylamine hydrochloride (271 mg, 3.90 mmol) was added followed by diisopropylethylamine (880 μl, 5.20 mmol). The resulting mixture was stirred at 20 ° C. for 16 h, poured into ethyl acetate (150 ml), washed with pH 7 phosphate buffer solution (3 × 50 ml), saturated aqueous sodium chloride (50 ml) and dried (Na ₂ SO ₄ ) It concentrated under reduced pressure. The residue was recrystallized from dichloromethane / diisopropyl ether to give the title compound (275 mg, 24%) as a colorless solid. Sample by purified hplc (Phenomenex C18 Magellan column, 150 × 20 mm, 5 μpacking, 20 ml / min acetonitrile: aqueous phosphate buffer (8.3 mM, pH 7.2) = 1: 1, retention time 13.5 minutes) (130 mg) was further purified, triturated with diisopropyl ether, filtered and dried in vacuo at 50 ° C. to give 50 mg of a white solid.

m.p. 136-137 ℃

R _f 0.39 (dichloromethane: methanol: saturated aqueous ammonia = 90: 10: 1)

Elemental analysis for _{C 33 H 40 FN 3 O 5} · 0.25H 2 O

Found: C, 68.14; H, 6.94; N, 7.21;

Theoretical value: C, 68.08; H, 7.01; N, 7.22%

<Example 5>

N1-[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl]-(N4-hydroxy)-(2R) -2- [3 -(3-methyl-4-phenoxyphenyl) propyl} butanediamide

(3R) -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl in anhydrous dimethylformamide (5 ml) at 20 ° C. nitrogen) ) Propyl] amino} carbonyl) -6- (3-methyl-4-phenoxyphenyl) hexanoic acid (Preparation 6) (640 mg, 1.15 mmol) and diisopropylethylamine (198 μl, 1.15 mmol) To a stirred solution, N-[(dimethylamino) -1H-1,2,3-triazolo [4,5-b] pyridin-1-ylmethylene] -N-methylmethanium hexafluorophosphate N-oxide ( 655 mg, 1.72 mmol) was added. After 25 minutes, hydroxylamine hydrochloride (239 mg, 3.44 mmol) was added followed by diisopropylethylamine (792 μl, 4.60 mmol). The resulting mixture was stirred for 48 h at 20 ° C., poured into ethyl acetate (150 ml), washed with pH 7 phosphate buffer solution (3 × 50 ml), saturated aqueous sodium chloride (50 ml) and dried (MgSO ₄ ) Concentrated under reduced pressure. The crude product was purified by flash chromatography. First, chromatography was performed by eluting with dichloromethane: methanol: concentrated aqueous ammonia = 90: 10: 1 to give a yellow oil. Further purification by flash chromatography (eluting with dichloromethane: methanol = 95: 5) gave an orange oil which was crystallized from dichloromethane / diisopropyl ether to give the title compound (25 mg, 4%).

R _f 0.27 (Dichloromethane: Methanol = 90: 10)

<Example 6>

N1-[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl]-(3S) -ethoxy- (2R) -2- [3 -(3-fluoro-4-phenoxyphenyl) propyl]-(N4-hydroxy) butanediamide

(2S, 3R) -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] aminocarbide in anhydrous dimethylformamide (2.5 ml) at 0 ° C. nitrogen). Carbonyl) propyl] aminocarbonyl) -2-ethoxy-6- (3-fluoro-4-phenoxyphenyl) hexanoic acid (Preparation Example 8) (94 mg, 0.155 mmol) and diisopropylethylamine (54 Μl, 0.31 mmol) in a stirred solution of N-[(dimethylamino) -1H-1,2,3-triazolo [4,5-b] pyridin-1-ylmethylene] -N-methylmethanium hexafluoro Lophosphate N-oxide (88 mg, 0.232 mmol) was added. After 45 minutes, hydroxylamine hydrochloride (32 mg, 0.465 mmol) was added followed by diisopropylethylamine (81 μl, 0.465 mmol). The resulting mixture was stirred at 0 ° C. for 5 h, poured into ethyl acetate (50 ml), washed with pH 7 phosphate buffer solution (3 × 30 ml), saturated aqueous sodium chloride (30 ml) and dried (MgSO ₄ ) Concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with dichloromethane: methanol: concentrated aqueous ammonia = 95: 5: 0.5) to afford the title compound (43 mg, 34%) as a colorless foam.

R _f 0.32 (dichloromethane: methanol: saturated aqueous ammonia = 95: 5: 0.5)

_{C 35 H 44 FN 3 O 6} · 0.5H ₂ O Elemental analysis

Found: C, 66.79; H, 7.05; N, 6.66;

Theoretical value: C, 66.65; H, 7. 17; N, 6.66%

<Example 7>

(2S, 3R) -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl] amino} carbonyl) -6- [(3-methyl-4-phenyl) phenyl] -2-propylhexanoic acid

According to the method of Example 1 tert-butyl (2S, 3R) -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl ) Propyl] amino} carbonyl) -6- [3-methyl- (4-phenyl) phenyl] -2-propylhexanoate (Preparation 13) (360 mg, 0.56 mmol) in trifluoromethane in anhydrous dichloromethane After treatment with roacetic acid, recrystallization from methanol gave the title compound (163 mg, 50%) as a colorless solid. A second product (45 mg, 14%) was obtained from methanol in the mother liquor.

m.p. 212-215 ° C (from methanol)

R _f 0.4 (dichloromethane / methanol / acetic acid = 90: 10: 1)

Elemental Analysis of C ₃₇ H ₄₈ N ₂ O ₄ 0.33MeOH1.25H ₂ O

Found: C, 72.60; H, 8.14; N, 4.59;

Theoretical value: C, 72.62; H, 8. 45; N, 4.54%

<Example 8>

N1-[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl]-(N4-hydroxy)-(2R) -2- {3 -[3-methyl-4-phenyl) phenyl] propyl}-(3S) -propylbutanediamide

According to the method of Example 4, (2S, 3R) -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl] Amino} carbonyl) -6-[(3-methyl-4-phenyl) phenyl] -2-propylhexanoic acid (Example 7) (130 mg, 0.22 mmol) was added to hydroxylamine hydrochloride (45.9 mg, 0.66 mmol ) Was reacted at 20 ° C. for 15 hours and then subjected to the same finish, and the crude product was triturated with ether to give the title compound (64 mg, 49%) as a colorless solid.

R _f 0.31 (dichloromethane: methanol: concentrated acetic acid = 90: 10: 1)

Elemental analysis for _{C 37 H 49 N 3 O 4} · 0.75H 2 O

Found: C, 72.14; H, 8. 18; N, 6.85;

Theoretical value: C, 72.46; H, 8. 30; N, 6.85%

<Example 9>

(N4, 3S) -dihydroxy-N1-[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl]-(2R) -2 -[3- (3-fluoro-4-phenoxyphenyl) propyl] butanediamide

To a solution of anhydrous hydroxylamine hydrochloride (45 mg, 0.67 mmol) in anhydrous methanol (1 ml) under room temperature nitrogen was added sodium methoxide (35 mg, 0.67 mmol). The mixture was stirred for 2 hours and filtered quickly through an Arbocel filtration aid pad and washed with anhydrous methanol (1 ml). (2R) -2-[(4S) -2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl] -N-[(1S) -2,2 in anhydrous methanol (1 ml) -Dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl] -5-[(3-fluoro-4-phenoxy) phenyl] pentanamide (Preparation 15) (103 mg, 0.16 mmol) was added and the mixture was stirred at rt for 18 h. The solution is concentrated under reduced pressure and the residue is eluted with methanol / water = 4: 1 and flashed over C ₁₈ silanized silica gel (40-63 μ) followed by normal silica gel (elution with dichloromethane: methanol). Purification by chromatography. The product was obtained as a colorless solid (25 mg, 26%).

m.p. 90-95 ℃

R _f 0.38 (dichloromethane: methanol = 90: 10)

Elemental analysis for _{C 35 H 40 FN 3 O 5} · 0.4H 2 O

Found: C, 65.94; H, 6.89; N, 6.95;

Theoretical value: C, 65.96; H, 6. 84; N, 6.99%

<Example 10>

(N4, 3S) -dihydroxy-N1-[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl]-(2R) -2 -{3- [3-methyl- (4-phenyl) phenyl] propyl} butanediamide

According to the method of Example 9, (2R) -2-[(4S) -2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl] -N-[(1S) -2, 2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl] -5-[(3-methyl-4-phenyl) phenyl] pentanamide (Preparation 16) (440 mg , 0.73 mmol) was reacted with hydroxylamine at room temperature for 18 hours. The solution was concentrated under reduced pressure and the residue was purified by flash chromatography (C ₁₈ silanated silica gel (40-63 μL), eluting with methanol / water = 4: 1 then 5: 1) to give a colorless solid (339 mg, 81%) was obtained.

m.p. 95-97 ℃

R _f 0.16 (Dichloromethane: Methanol = 95: 5)

_{C 34 H 43 N 3 O 5} · 0.25H ₂ O Elemental analysis

Found: C, 70.50; H, 7. 58; N, 7.23;

Theoretical value: C, 70.62; H, 7. 58; N, 7.27%

<Example 11>

(2R) -N1-[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl] -2- {3- [3-fluoro- (4-phenyl) phenyl] propyl}-(N4-hydroxy) butanediamide

a) According to the method of Example 2, (3R) -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl] Amino} carbonyl) -6-[(3-fluoro-4-phenyl) phenyl] hexanoic acid (Preparation 17) (426 mg, 0.78 mmol) to O-allylhydroxylamine hydrochloride (128 mg, 1.17 mmol) ). The crude product was purified by flash chromatography (eluent eluting with hexanes: isopropanol) and then triturated with ether and ethyl acetate to give (2R) -N1-[(1S) -2,2-dimethyl-1- ( {[(1R) -1-phenylethyl] amino} carbonyl) propyl] -2- {3- [3-fluoro- (4-phenyl) phenyl] propyl}-(N4-3-propenyloxy) butane Diamide (260 mg, 55%) was obtained.

m.p. 182-186 ℃

R _f 0.32 (hexane: isopropanol = 10: 1)

_{C 36 H 44 FN 3 O 4} · 0.5H ₂ O Elemental analysis

Found: C, 70.91; H, 7. 33; N, 6.84;

Theoretical value: C, 70.80; H, 7. 43; N, 6.88%

b) (2R) -N1-[(1S) -2,2-dimethyl-1-({[(1R) under a palladium catalyst in ethanol / water (4: 1, 5 ml) according to the method of example 2 -1-phenylethyl] amino} carbonyl) propyl] -2- {3- [3-fluoro- (4-phenyl) phenyl] propyl}-(N4-3-propenyloxy) butanediamide (210 mg , 0.35 mmol) was reacted with ammonium formate (110 mg, 1.75 mmol) at reflux for 2 hours. After finishing treatment, the residue was purified by flash chromatography (dichloromethane: methanol: gradient elution with concentrated aqueous ammonia) and then triturated with ether to give (2R) -N1-[(1S) -2,2 as a colorless solid. -Dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl] -2- {3- [3-fluoro- (4-phenyl) phenyl] propyl}-(N4-hydrate Roxy) butanediamide (120 mg, 61%) was obtained.

R _f 0.25 (dichloromethane: methanol: concentrated aqueous ammonia = 90: 10: 1)

Elemental analysis for _{C 33 H 40 FN 3 O 4} · 0.25H 2 O

Found: C, 70.02; H, 7. 25; N, 7.52;

Theoretical value: C, 70.00; H, 7. 21; N, 7.42%

<Example 12>

(3R) -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl] amino} carbonyl)-(2S)- Ethoxy-6-[(3-methyl-4-phenyl) phenyl] hexanoic acid

Tetrahydrofuran: water = 3: 2 methyl (2S, 3R) -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl]] Amino} carbonyl) propyl] amino} carbonyl) -2-ethoxy-6-[(3-methyl-4-phenyl) phenyl] -hexanoate (Preparation 18) (384 mg, 0.64 mmol) To the lithium hydroxide hydrate (30 mg, 0.71 mmol) was added and the mixture was stirred at room temperature for 2 hours. This solution was acidified with 1M hydrochloric acid and extracted with ethyl acetate (3 × 30 ml). The combined extracts were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. Trituration with ether gave the title compound (196 mg, 52%) as a colorless solid.

_{C 36 H 46 N 2 O 5} · 0.25H ₂ O Elemental analysis

Found: C, 73.11; H, 7.89; N, 4.79;

Theoretical value: C, 73.12; H, 7.92; N, 4.74%

<Example 13>

N1-[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl]-(3S) -ethoxy- (N4-hydroxy)-( 2R) -2- {3- [3-methyl- (4-propyl) phenyl] propyl} butanediamide

(2S, 3R) -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} in anhydrous dimethylformamide (3 ml) at 0 ° C. nitrogen). Carbonyl) propyl] amino} carbonyl) -2-ethoxy-6-[(3-methyl-4-phenyl) phenyl] -hexanoic acid (Example 12) (169 mg, 0.29 mmol) with diisopropylethyl To a stirred solution of amine (50 μl, 0.29 mmol) N-[(dimethylamino) -1H-1,2,3-triazolo [4,5-b] pyridin-1-ylmethylene] -N-methylmethanini Um hexafluorophosphate N-oxide (164 mg, 0.43 mmol) was added. After 60 minutes hydroxylamine hydrochloride (60 mg, 0.86 mmol) was added followed by diisopropylethylamine (81 μl, 0.465 mmol). The resulting mixture was stirred at 20 ° C. for 16 h, diluted with ether and washed with water. The aqueous layer was extracted with ether (twice) and ethyl acetate. The combined organic solution was washed with water, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was repeatedly purified by flash chromatography (dichloromethane: methanol: concentrated aqueous ammonia = 97.5: 2.5: 0.5 followed by 96: 4: 0.5) to afford the title compound (20 mg, 11%) as a white foam.

R _f 0.25 (dichloromethane: methanol: concentrated aqueous ammonia = 90: 10: 1)

HRMS of C ₃₆ H ₄₇ NaN ₃ (positive ion electrospray)

Found: m / z = 624.3403

Theoretical Value: m / z = 624.3413

<Example 14>

(3R) -3-({[(1S) -2,2-dimethyl-1-({[(1S) -2-methoxy-1-phenylethyl] amino} carbonyl) propyl] amino} carbonyl) -6-[(3-methyl-4-phenyl) phenyl] hexanoic acid

According to the method of Example 1 tert-butyl (3R) -3-({[(1S) -2,2-dimethyl-1-({[(1S) -2-methoxy-1-phenylethyl] amino } Carbonyl) propyl] amino} carbonyl) -6- [3-methyl- (4-phenyl) phenyl] hexanoate (Preparation 19) (535 mg, 0.85 mmol) was added to trifluoroacetic acid in anhydrous dichloromethane. Treated at room temperature for 2 hours. The residue was dissolved in toluene, concentrated under reduced pressure (twice) and recrystallized from ethyl acetate to give a colorless solid (387 mg, 80%).

m.p. 184-186 ° C (from ethyl acetate)

R _f 0.47 (hexane: ether: acetic acid = 50: 50: 1)

Elemental Analysis of C ₃₅ H ₄₄ N ₂ O ₅

Found: C, 73.32; H, 7.73; N, 4.80;

Theoretical value: C, 73.40; H, 7. 74; N, 4.89%

<Example 15>

(3R) -3-({[(1S) -2,2-dimethyl-1-({[(1S) -2-methoxy-1-phenylethyl] amino} carbonyl) propyl] amino} carbonyl) -6-[(3'-methoxy-2-methylbiphen-4-yl) hexanoic acid

According to the method of Example 1 tert-butyl (3R) -3-({[(1S) -2,2-dimethyl-1-({[(1S) -2-methoxy-1-phenylethyl] amino } Carbonyl) propyl] amino} carbonyl) -6- (3'-methoxy-2-methylbiphen-4-yl) hexanoate (Preparation 21) (660 mg, 1.0 mmol) in anhydrous dichloromethane Treated with trifluoroacetic acid at room temperature for 3 hours. The residue was dissolved in toluene, concentrated under reduced pressure (twice) and recrystallized from ethyl acetate to give a colorless solid (326 mg, 54%). The mother liquor was recrystallized to give an additional 107 mg (18%).

m.p. 155.5-157.5 ° C (from ethyl acetate)

R _f 0.34 (hexane: ether: acetic acid = 50: 50: 1)

Elemental Analysis of C ₃₆ H ₄₆ N ₂ O ₆

Found: C, 71.77; H, 7.69; N, 4.61;

Theoretical value: C, 71.73; H, 7.69; N, 4.65%

<Example 16>

(2R) -N-1-[(1S) -2,2-dimethyl-1-({[(1S) -2-methoxy-1-phenylethyl] amino} carbonyl) propyl] -2- {3 -[(3-methyl-4-phenyl) phenyl] propyl}-(N-4-hydroxy) butanediamide

a) According to the method of Example 2, (3R) -3-({[(1S) -2,2-dimethyl-({[(1S) -2-methoxy-1-phenylethyl] amino} carbonyl ) Propyl] amino} carbonyl) -6-[(3-methyl-4-phenyl) phenyl] hexanoic acid (Example 14) (347 mg, 0.61 mmol) was added to O-allylhydroxylamine hydrochloride (81 mg, 0.73 mmol). The crude product was purified by flash chromatography (eluting with hexanes: ethyl acetate = 2: 1), then triturated with ether and ethyl acetate to give (2R) -N1-[(1S) -2,2-dimethyl as a white solid. -1-({[(1S) -2-methoxy-1-phenylethyl] amino} carbonyl) propyl] -2- {3-[(3-methyl-4-phenyl) phenyl] propyl}-(N4 3-propenyloxy) butanediamide (306 mg, 80%) was obtained.

m.p. 117-120 ℃

R _f 0.28 (hexane: ethyl acetate = 1: 2)

b) (2S) -N1-[(1S) -2,2-dimethyl-1-({[(1S) -2-methoxy-1-phenylethyl] amino} carbonyl) propyl] -2- {3 -[(3-methyl4-phenyl) phenyl] propyl}-(N4-3-propenyloxy) butanediamide (300 mg, 0.48 mmol) and ammonium formate (300 mg, 4.76 mmol) were stirred at high temperature. In ethanol / water (4: 1, 6 ml) to give a colorless solution. A solution of palladium acetate (4 mg, 0.018 mmol) and triphenylphosphine (9.6 mg, 0.037 mmol) in ethanol / water (4: 1, 2 ml) was added and the mixture was heated at reflux for 60 minutes. After cooling, the brown solution was diluted with ethyl acetate (100 ml), washed with saturated aqueous sodium chloride (2 x 50 ml), dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (C ₁₈ silanated silica gel (40-63 μ), eluting with methanol: water = 4: 1) and triturated with diisopropyl ether to give (2R) -N1-[(1S ) -2,2-dimethyl-1-({[(1S) -1-methoxy-1-phenylethyl] amino} carbonyl) propyl] -2- {3-[(3-methyl-4-phenyl) Phenyl] propyl}-(N4-hydroxy) butanediamide (226 mg, 80%) was obtained as a white solid.

m.p. 92-96 ℃

R _f 0.57 (dichloromethane: methanol: concentrated aqueous ammonia = 90: 10: 1)

Elemental analysis for _{C 35 H 45 N 3 O 5} · 0.25H 2 O

Found: C, 70.95; H, 7.85; N, 7.00;

Theoretical value: C, 70.98; H, 7. 74; N, 7.09%

<Examples 17 and 18>

(N4, 3S) -dihydroxy-N1-[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl]-(2R) -2 -{3- [4- (4-cyanophenyl) -3-methylphenyl] propyl} butanediamide and (N4,3S) -dihydroxy-N1-[(1S) -2,2-dimethyl-1- ({[(1R) -1-phenylethyl] amino} carbonyl) propyl]-(2R) -2- {3- [4- (4-hydroxyamidino) phenyl-3-methylphenyl] propyl} butanedia mid

According to the method of Example 9, (2R) -5-{[4- (4-cyanophenyl) -3-methyl] phenyl} -2-[(4S) -2,2-dimethyl-5-oxo- 1,3-dioxolan-4-yl] -N-[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl] pentanamide (manufacture Example 22) (384 mg, 0.62 mmol) was reacted with hydroxylamine for 18 hours at room temperature. The solution was concentrated under reduced pressure and the residue was purified by column chromatography (C ₁₈ silanated silica gel (40-63 μ), eluting with methanol: water = 70: 30 followed by 80:20) to give two fractions. Got it. The first eluted product was (N4,3S) -dihydroxy-N1-[(1S) -2,2-dimethyl-1-({[(1R)) of R _f 0.38 (dichloromethane: methanol = 90: 10). -1-phenylethyl] amino} carbonyl) propyl]-(2R) -2- {3- [4- (4-cyanophenyl) -3-methylphenyl] propyl} butanediamide, which is diiso Trituration with propyl ether gave a white solid (115 mg, 31%).

m.p. 103-109 ℃

Elemental Analysis of C ₃₅ H ₄₂ N ₄ O ₅ 0.1EtOAc0.4H ₂ O

Found: C, 69.26; H, 7. 15; N, 9.10;

Theoretical value: C, 69.16; H, 7. 15; N, 9.11%

The second eluted product was (N4,3S) -dihydroxy-N1-[(1S) -2,2-dimethyl-1-({[(1R) of R _f 0.20 (dichloromethane: methanol = 90: 10). ) -1-phenylethyl] amino} carbonyl) propyl]-(2R) -2- {3- [4- (4-hydroxyamidino) phenyl-3-methylphenyl] propyl} butanediamide white identified Solid (84 mg, 21%).

m.p. 131-135 ℃

Elemental Analysis of C ₃₅ H ₄₅ N ₅ O ₆ 0.1C ₃ OH0.9H ₂ O

Found: C, 64.86; H, 7. 21; N, 10.28;

Theoretical value: C, 64.74; H, 7.31; N, 10.75%

<Example 19>

(N4,3S) -dihydroxy-N1-[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl]-(2R) -2 -{3- [4- (3-cyanophenyl) -3-methylphenyl] propyl} butanediamide

To a solution of anhydrous hydroxylamine hydrochloride (56 mg, 0.80 mmol) in anhydrous methanol (1 ml) under room temperature nitrogen was added sodium methoxide (43 mg, 0.80 mmol). The mixture was stirred for 2.5 h and filtered quickly through an arbocell filtration aid pad and washed with anhydrous methanol (1 ml). (2R) -5-{[4- (3-cyanophenyl) -3-methyl] phenyl} -2-[(4S) -2,2-dimethyl-5-oxo-1 in anhydrous methanol (1 ml) , 3-dioxolan-4-yl] -N-[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl] pentanamide (Preparation Example 24) (123 mg, 0.20 mmol) was added to the mixture at 4 ° C. and stirred for 5 minutes. The mixture was warmed to room temperature and stirred for 9 hours. The solution was concentrated under reduced pressure and the residue was purified by column chromatography (C ₁₈ silanated silica gel (40-63 μ), eluting with methanol: water = 3: 1). The residue was boiled with ethanol followed by ethyl acetate and triturated with diisopropyl ether to give the title compound (58 mg, 48%) as an amorphous white solid. There was no apparent melting point.

R _f 0.11 (dichloromethane: methanol: concentrated aqueous ammonia = 90: 10: 1)

Elemental analysis for _{C 35 H 42 N 4 O 5} · 0.5H 2 O

Found: C, 69.12; H, 7. 20; N, 9.04;

Theoretical value: C, 69.17; H, 7.13; N, 9.22%

<Example 20>

(2R) -2- {3- [4- (3-carbamoylphenyl) -3-methylphenyl] propyl}-(N4,3S) -dihydroxy-N1-[(1S) -2,2-dimethyl -1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl] butanediamide

According to the method of Example 19, (2R) -5-{[4- (3-carbamoylphenyl) -3-methyl] phenyl-2-[(4S) -2,2-dimethyl-5-oxo- 1,3-dioxolan-4-yl] -N-[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl] pentanamide (manufacture Example 26) (126 mg, 0.20 mmol) was reacted with hydroxylamine for 13 hours at room temperature. This solution was concentrated under reduced pressure and the residue was purified by column chromatography (C ₁₈ silanated silica gel (40-63 μ), eluting with methanol: water = 3: 2). The residue was boiled with ethanol then ethyl acetate and triturated with diethyl ether to give the title compound (74 mg, 60%) as a white solid.

m.p. 85-100 ℃

R _f 0.04 (dichloromethane: methanol: concentrated aqueous ammonia = 90: 10: 1)

Elemental analysis for _{C 35 H 44 N 4 O 6} · 1.33H 2 O

Found: C, 65.35; H, 7. 29; N, 8.57;

Theoretical value: C, 65.61; H, 7. 34; N, 8.74%

<Example 21>

(3R) -3-[({({[(1S) -2-methoxy-1-phenylethyl] amino} carbonyl)-[(1S) -2-methyl] -1-propyl} amino) carbonyl ] -6- [3-methyl- (4-phenyl) phenyl] hexanoic acid

According to the method of Example 1, tert-butyl (3R) -3-[({({[(1S) -2-methoxy-1-phenylethyl] amino} carbonyl)-[(1S) -2- Methyl] -1-propyl} amino) carbonyl] -6- [3-methyl- (4-phenyl) phenyl] hexanoate (Preparation 28) (700 mg, 1.14 mmol) was added to trifluoro in anhydrous dichloromethane. Treated with acetic acid at room temperature for 4 hours. The residue was boiled with toluene (twice) and recrystallized from diethyl ether to give the title compound (506 mg, 79%) as a colorless solid.

m.p. 141-144 ℃

R _f 0.28 (pentane: ethyl acetate: acetic acid = 50: 50: 1)

Elemental Analysis of C ₃₄ H ₄₂ N ₂ O ₅

Found: C, 72.86; H, 7.52; N, 5.04;

Theoretical values: C, 73.09; H, 7. 58; N, 5.01%

<Example 22>

(3R) -3-[({({[(1S) -2-methoxy-1-phenylethyl] amino} carbonyl)-(1S) -2-pentylethyl] amino} carbonyl) -6- [ 3-Methyl- (4-phenyl) phenyl] hexanoic acid

According to the method of Example 1, tert-butyl (3R) -3-[({({[(1S) -2-methoxy-1-phenylethyl] amino} carbonyl)-(1S) -2-pentyl Ethyl] amino} carbonyl) -6- [3-methyl- (4-phenyl) phenyl] hexanoate (Preparation 30) (920 mg, 1.39 mmol) was diluted with trifluoroacetic acid in anhydrous dichloromethane to 4 at room temperature. Treated for hours. The residue was boiled with toluene (twice) and recrystallized from diethyl ether to give the title compound (665 mg, 79%) as a colorless solid.

m.p. 152-157 ℃

R _f 0.27 (pentane: ethyl acetate: acetic acid = 50: 50: 1)

Elemental Analysis of C ₃₈ H ₄₂ N ₂ O ₅

Found: C, 75.02; H, 6.96; N, 4.63;

Theoretical value: C, 75.22; H, 6.98; N, 4.62%

<Example 23>

(3R) -3-({[(1S) -2,2-dimethyl-1-{[(1R) -1- (4-pyridyl) ethylamino] carbonyl} propyl] amino} carbonyl) -6 -[(3-methyl-4-phenyl) phenyl] hexanoic acid hydrochloride

Tert-butyl- (3R) -3-({[(1S) -2,2-dimethyl-1-{[(1R) -1- (4-pyridyl) in dioxane (15 ml) at 0 ° C. nitrogen. Saturated hydrogen chloride gas in a solution of ethylamino] carbonyl} propyl] amino} carbonyl) -6-[(3-methyl-4-phenyl) phenyl] hexanoate (Preparation 31) (285 mg, 0.47 mmol) Bubbling until The solution was stirred at 0 ° C. for 3 hours and then concentrated under reduced pressure. The residue was triturated with diethyl ether to give the title compound (390 mg, 88%) as a white solid.

m.p. 132 ℃ (decomposition)

R _f 0.16 (ethyl acetate: hexane: acetic acid = 75:25: 1)

Elemental analysis for _{C 33 H 41 N 3 O 4} · HCl · 1.5H 2 O

Found: C, 65.43; H, 7. 28; N, 6.72;

Theoretical value: C, 65.28; H, 7.47; N, 6.92%

<Example 24>

N1-[(1S) -2,2-dimethyl-1-([(1R) -1- (3-pyridyl) ethylamino] carbonyl) propyl]-(N4-hydroxy)-(2R) -2 -{3- [3-methyl- (4-phenyl) phenyl] propyl} butanediamide

a) According to the method of Example 2, (3R) -3-({[(1S) -2,2-dimethyl-{[(1R) -1- (3-pyridyl) ethylamino] carbonyl) propyl ] Amino} carbonyl) -6-[(3-methyl-4phenyl) phenyl] -hexanoic acid (Preparation 32) (330 mg, 0.57 mmol) was added to O-allylhydroxylamine hydrochloride (76 mg, 0.68 mmol). ). The crude product was purified by recrystallization from hot ethyl acetate to give N1-[(1S) -2,2-dimethyl-1-([(1R) -1- (3-pyridyl) ethylamino] carbonyl) propyl as a white solid. ]-(N4-3-propenyloxy)-(2R) -2- {3- [3-methyl- (4-phenyl) phenyl] propyl} butanediamide (219 mg, 64%) was obtained.

m.p. 187-189 ℃

R _f 0.21 (ethyl acetate)

b) N1-[(1S) -2,2-dimethyl-1-([(1R) -1- (3) under palladium catalyst in ethanol / water (4: 1, 8 ml) according to the method of example 2 -Pyridyl) ethylamino] carbonyl) propyl]-(N4-3-propenyloxy)-(2R) -2- {3- [3-methyl- (4-phenyl) phenyl] propyl} butanediamide ( 219 mg, 0.37 mmol) was reacted with ammonium formate (230 mg, 3.66 mmol) under reflux for 1.25 h. After finishing treatment, the residue was purified by column chromatography (C ₁₈ silanated silica gel (40-63 μ), eluting with methanol: water = 4: 1) and then triturated with diisopropyl ether to give a white solid. N1-[(1S) -2,2-dimethyl-1-([(1R) -1- (3-pyridyl) ethylamino] carbonyl) propyl]-(N4-hydroxy)-(2R) -2 -{3- [3-methyl- (4-phenyl) phenyl] propyl} butanediamide (122 mg, 60%) was obtained.

m.p. 112-114 ℃

R _f 0.33 (C ₁₈ silanized silica, methanol: water = 5: 1)

Elemental Analysis of C ₃₃ H ₄₂ N ₄ O ₄ 0.33H ₂ O0.33DIPE

Found: C, 70.13; H, 7.83; N, 9.48;

Theoretical value: C, 70.20; H, 7.80; N, 9.63%

<Example 25>

(N4, 3S) -dihydroxy-N1-[(1S) -2,2-dimethyl-1-({[(1R) -1- (4-pyridyl) ethyl] amino} carbonyl) propyl]- (2R) -2- {3- [3-methyl- (4-phenyl) phenyl] propyl} butanediamide

J. Amer. Chem. Soc., 1973, 95, 811] (R)-by recrystallization of the (-)-tartaric acid salt of racemic amine ([α] _D ²⁰ = -16.7 ° (c = 0.20, H ₂ O)). (+)-1- (4-pyridyl) ethylamine was prepared. The free base was liberated by dissolving tartarate in an excess of aqueous sodium hydroxide saturated with sodium chloride and extracting several times with dichloromethane. The free base was used immediately without purification.

a) (2R) -N-[(1S) -1- (carboxy) -2,2-dimethylpropyl] -2-[(4S) -2,2- in anhydrous dichloromethane (4 ml) at 0 ° C. nitrogen. Dimethyl-5-oxo-1,3-dioxolan-4-yl] -5-[(3-methyl-4-phenyl) phenyl] pentanamide (Preparation 33) (198 mg, 0.40 mmol), (R) To a stirred solution of-(+)-1- (4-pyridyl) ethylamine (49 mg, 0.40 mmol) and collidine (53 μL, 0.40 mmol), 7-azabenzotriazol-1-yloxytris (pi Lolidino) phosphonium hexafluorophosphate (208 mg, 0.40 mmol) was added. After 1 hour, the solution was stirred at 20 ° C. for 3 hours. Pour this mixture into ethyl acetate (100 ml) and water (100 ml), solid sodium chloride ?? Phase separated by addition. The layers were separated and the organic layer was washed with 5% aqueous sodium hydrogen carbonate (2 x 75 ml) and more solid sodium chloride was added. The organic solution was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane: ethyl acetate = 5: 1 to 1: 5 gradient eluting) and triturated with diisopropyl ether to give (2R) -2-[(4S) -2,2 as a white solid. -Dimethyl-5-oxo-1,3-dioxolan-4-yl] -N-[(1S) -2,2-dimethyl-1-({[(1R) -1- (4-pyridyl) ethyl ] Amino} carbonyl) propyl] -5-[(3-methyl-4-phenyl) phenyl] pentanamide (104 mg, 43%) was obtained.

m.p. 167-170 ℃

R _f 0.10 (hexane: ethyl acetate = 1: 3)

_{C 36 H 45 N 3 O 5} · 1.2H 2 O · 0.13EtOAc Elemental analysis for

Found: C, 69.04; H, 7.31; N, 6.68;

Theoretical value: C, 69.32; H, 7.71; N, 6.64%

b) (2R) -2-[(4S) -2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl] -N (from above a) according to the method of example 19 -[(1S) -2,2-dimethyl-1-({[(1R) -1- (4-pyridyl) ethyl] amino} carbonyl) propyl] -5-[(3-methyl-4-phenyl ) Phenyl] pentanamide (86 mg, 0.14 mmol) was reacted with hydroxylamine for 18 hours at room temperature. This solution was concentrated under reduced pressure and purified by column chromatography (C ₁₈ silanated silica gel (40-63 μ), eluting with methanol: water = 3: 1). The residue was boiled with ethanol followed by ethyl acetate and triturated with diisopropyl ether to give the title compound (45 mg, 56%) as a white solid.

m.p. 100-110 ℃

R _f 0.10 (dichloromethane: methanol: concentrated aqueous ammonia = 90: 10: 1)

Elemental analysis for _{C 33 H 42 N 4 O 5} · 0.5H 2 O

Found: C, 67.88; H, 7. 44; N, 9.42;

Theoretical value: C, 67.90; H, 7. 43; N, 9.06%

<Example 26>

(N4, 3S) -dihydroxy-N1-[(1S) -2,2-dimethyl-1-({[(1R) -1- (3-pyridyl) ethyl] amino} carbonyl) propyl]- (2R) -2- {3- [3-methyl- (4-phenyl) phenyl] propyl} butanediamide

J. Amer. Chem. Soc., 1973, 95, 811] (R)-by recrystallization of the (-)-tartaric acid salt of racemic amine ([α] _D ²⁰ = -20.1 ° (c = 1.67, H ₂ O)) (+)-1- (3-pyridyl) ethylamine was prepared. The free base was liberated by dissolving tartarate in excess 1 M aqueous sodium hydroxide saturated with sodium chloride and extracting several times with dichloromethane. The free base was used immediately without purification.

a) Example 25 According to the method of (a), (2R) -N-[(1S) -1- (carboxy) -2,2-dimethylpropyl] -2-[(4S) -2,2-dimethyl -5-oxo-1,3-dioxolan-4-yl] -5-[(3-methyl-4-phenyl) phenyl] pentanamide (Preparation 33) (86 mg, 0.14 mmol) was added to (R)- After reacting with (+)-1- (3-pyridyl) ethylamine free base (49 mg, 0.40 mmol) for 3 hours at room temperature, the same finishing treatment was carried out, and the crude product was triturated with diisopropyl ether to give white (2R) -2-[(4S) -2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl] -N-[(1S) -2,2-dimethyl-1- as a solid ({[(1R) -1- (3-pyridyl) ethyl] amino} carbonyl) propyl] -5-[(3-methyl-4-phenyl) phenyl] pentanamide (165 mg, 69%) was obtained. .

m.p. 172-176 ℃

R _f 0.10 (hexane: ethyl acetate = 1: 3)

b) (2R) -2-[(4S) -2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl] -N (from above a) according to the method of example 19 -[(1S) -2,2-dimethyl-1-({[(1R) -1- (3-pyridyl) ethyl] amino} carbonyl) propyl] -5-[(3-methyl-4-phenyl ) Phenyl] pentanamide (142 mg, 0.24 mmol) was reacted with hydroxylamine for 17 hours at room temperature. The solution was concentrated under reduced pressure and purified by column chromatography (C ₁₈ silanated silica gel (40-63 μ), eluting with methanol: water = 60: 40 to 80:20) to give a pale yellow solid. This solid was purified repeatedly by reverse phase chromatography (eluting with methanol: water = 75: 25). The product was boiled with ethanol then ethyl acetate and triturated with diisopropyl ether to give the title compound (50 mg, 36%) as a white solid.

m.p. 85-95 ℃

R _f 0.11 (dichloromethane: methanol: concentrated aqueous ammonia = 90: 10: 1)

Elemental analysis for _{C 33 H 42 N 4 O 5} · 0.67H 2 O

Found: C, 67.52; H, 7. 44; N, 9.52;

Theoretical value: C, 67.57; H, 7. 44; N, 9.55%

<Example 27>

(N4, 3S) -dihydroxy-N1-[(1S) -2,2-dimethyl-1-({[(1S) -2-hydroxy-1-phenylethyl] amino} carbonyl) propyl]- (2R) -2- {3- [3-methyl- (4-phenyl) phenyl] propyl} butanediamide

a) Example 25 According to the method of (a), (2R) -N-[(1S) -1- (carboxy) -2,2-dimethylpropyl] -2-[(4S) -2,2-dimethyl -5-oxo-1,3-dioxolan-4-yl] -5-[(3-methyl-4-phenyl) phenyl] pentanamide (Preparation 33) (150 mg, 0.30 mmol) was added to (S)- It was reacted with (+)-2-phenylglycinol (41 mg, 0.30 mmol) at room temperature for 3 hours. This mixture was poured into ethyl acetate (75 ml) and washed with 0.5 M aqueous sodium monophosphate (2 × 50 ml) (phase separated by addition of solid sodium chloride). The organic solution was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residual oil was triturated with diethyl ether to give (2R) -2-[(4S) -2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl] -N-[(1S as white solid. ) -2,2-dimethyl-1-({[(1S) -2-hydroxy-1-phenylethyl] amino} carbonyl) propyl] -5-[(3-methyl-4-phenyl) phenyl] pentane Amide (80 mg, 43%) was obtained.

m.p. 206-209 ℃

R _f 0.33 (hexane: ethyl acetate: acetic acid = 50: 50: 1)

_{C 37 H 46 N 2 O 5} · 0.33H ₂ O Elemental analysis

Found: C, 71.46; H, 7.53; N, 4.59;

Theoretical value: C, 71.59; H, 7. 58; N, 4.51%

b) (2R) -2-[(4S) -2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl] -N (from above a) according to the method of example 19 -[(1S) -2,2-dimethyl-1-({[(1S) -2-hydroxy-1-phenylethyl] amino} carbonyl) propyl] -5-[(3-methyl-4-phenyl ) Phenyl] pentanamide (66 mg, 0.11 mmol) was reacted with hydroxylamine for 17 hours at room temperature. This solution was concentrated under reduced pressure and purified by column chromatography (C ₁₈ silanated silica gel (40-63 μ), eluting with methanol: water = 60: 40 to 80:20). The residue was boiled with ethanol followed by ethyl acetate and triturated with diisopropyl ether to give the title compound (35 mg, 54%) as a pale yellow solid.

m.p. 80-90 ℃

R _f 0.06 (dichloromethane: methanol: concentrated aqueous ammonia = 90: 10: 1)

_{C 34 H 43 N 3 O 6} · 0.67H 2 O · elemental analysis of 0.25DIPE

Found: C, 67.91; H, 7.71; N, 6.58;

Theoretical value: C, 67.99; H, 7.69; N, 6.70%

<Example 28>

(N4, 3S) -dihydroxy-N1-[(1S) -2,2-dimethyl-1-({[(1R) -2,3-hydro-1H-inden-1-yl] amino} carbonyl ) Propyl]-(2R) -2- {3- [3-methyl- (4-phenyl) phenyl] propyl} butanediamide

a) Example 25 According to the method of (a), (2R) -N-[(1S) -1- (carboxy) -2,2-dimethylpropyl] -2-[(4S) -2,2-dimethyl -5-oxo-1,3-dioxolan-4-yl] -5-[(3-methyl-4-phenyl) phenyl] pentanamide (Preparation 33) (150 mg, 0.30 mmol) to (R)- It was reacted with (-)-1-aminoindane (40 mg, 0.30 mmol) at room temperature for 3 hours. The mixture was poured into ethyl acetate (75 ml) and washed with 0.5 M aqueous sodium monophosphate (2 x 50 ml) and 5% aqueous sodium hydrogen carbonate (50 ml) (phase separated by addition of solid sodium chloride). The organic solution was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residual oil was purified by flash chromatography (hexane eluting with ethyl acetate = gradient of 10: 1 to 2: 1) and triturated with diisopropyl ether to give (2R) -2-[(4S) -2,2 as a white solid. -Dimethyl-5-oxo-1,3-dioxolan-4-yl] -N-[(1S) -2,2-dimethyl-1-({[(1R) -2,3-dihydro-1H- Inden-1-yl] amino} carbonyl) propyl] -5-[(3-methyl-4-phenyl) phenyl] pentanamide (135 mg, 74%) was obtained.

R _f 0.76 (hexane: ethyl acetate: acetic acid = 50: 50: 1)

Elemental Analysis of C ₃₈ H ₄₆ N ₂ O ₅ 0.33EtOAc

Found: C, 74.06; H, 7.61; N, 4.47;

Theoretical value: C, 73.81; H, 7. 66; N, 4.38%

b) (2R) -2-[(4S) -2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl] -N (from above a) according to the method of example 19 -[(1S) -2,2-dimethyl-1-({[(1R) -2,3-dihydro-1H-inden-1-yl] amino} carbonyl) propyl] -5-[(3- Methyl-4-phenyl) phenyl] pentanamide (105 mg, 0.17 mmol) was reacted with hydroxylamine for 17 hours at room temperature. This solution was concentrated under reduced pressure and purified by column chromatography (C ₁₈ silanated silica gel (40-63 μ), eluting with methanol: water = 60: 40 to 85:15). The residue was boiled with ethanol followed by ethyl acetate and triturated with diisopropyl ether to give the title compound (60 mg, 60%) as a pale yellow solid.

m.p. 100-120 ℃

R _f 0.10 (dichloromethane: methanol: concentrated aqueous ammonia = 90: 10: 1)

Elemental analysis for _{C 35 H 43 N 3 O 5} · 0.33H 2 O

Found: C, 70.94; H, 7. 50; N, 6.81;

Theoretical value: C, 71.05; H, 7. 44; N, 7.10%

<Example 29>

(N4, 3S) -dihydroxy-N1-[(1S) -2,2-dimethyl-1-({[(1S) -2-methoxy-1-phenylethyl] amino} carbonyl) propyl]- (2R) -2- {3- [3-methyl- (4-phenyl) phenyl] propyl} butanediamide

a) Example 25 According to the method of (a), (2R) -N-[(1S) -1- (carboxy) -2,2-dimethylpropyl] -2-[(4S) -2,2-dimethyl -5-oxo-1,3-dioxolan-4-yl] -5-[(3-methyl-4-phenyl) phenyl] pentanamide (Preparation 33) (198 mg, 0.40 mmol) (1S)- It was reacted with 2-methoxy-1-phenylethylamine (61 mg, 0.40 mmol) at room temperature for 3 hours. The mixture was poured into ethyl acetate (75 ml) and washed with 0.5 M aqueous sodium monophosphate (2 x 50 ml) and 5% aqueous sodium hydrogen carbonate (50 ml) (phase separated by addition of solid sodium chloride). The organic solution was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residual oil was purified by flash chromatography (hexane: ethyl acetate = 4: 1 to 1: 1 gradient eluting) and triturated with diisopropyl ether to give (2R) -2-[(4S) -2,2 as a white solid. -Dimethyl-5-oxo-1,3-dioxolan-4-yl] -N-[(1S) -2,2-dimethyl-1-({[(1S) -2-methoxy-1-phenylethyl ] Amino} carbonyl) propyl] -5-[(3-methyl-4-phenyl) phenyl] pentanamide (172 mg, 68%) was obtained.

R _f 0.53 (hexane: ethyl acetate: acetic acid = 50: 50: 1)

Elemental Analysis of C ₃₈ H ₄₈ N ₂ O ₆

Found: C, 72.41; H, 7.76; N, 4.50;

Theoretical value: C, 72.49; H, 7.72; N, 4.48%

b) (2R) -2-[(4S) -2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl] -N (from above a) according to the method of example 9 -[(1S) -2,2-dimethyl-1-({[(1S) -2-methoxy-1-phenylethyl] amino} carbonyl) propyl] -5-[(3-methyl-4-phenyl ) Phenyl] pentanamide (142 mg, 0.22 mmol) was reacted with hydroxylamine for 17 hours at room temperature. This solution was concentrated under reduced pressure and purified by column chromatography (C ₁₈ silanated silica gel (40-63 μ), eluting with methanol: water = 3: 1). The residue was boiled with ethanol followed by ethyl acetate and triturated with diisopropyl ether to give the title compound (109 mg, 82%) as a white solid.

m.p. 100-110 ℃

R _f 0.07 (dichloromethane: methanol: concentrated aqueous ammonia = 90: 10: 1)

_{C 35 H 45 N 3 O 6} · 0.5H ₂ O Elemental analysis

Found: C, 68.71; H, 7. 64; N, 6.65;

Theoretical value: C, 68.60; H, 7.57; N, 6.86%

<Example 30>

(N4, 3S) -dihydroxy-N1-[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl]-(2R) -2 -{3-[(3'-methoxy-2-methylbiphen-4-yl) propyl} butanediamide

a) Example 25 According to the method of (a), (2R) -N-[(1S) -1- (carboxy) -2,2-dimethylpropyl] -2-[(4S) -2,2-dimethyl -5-oxo-1,3-dioxolan-4-yl] -5-[(3'-methoxy-2-methylbiphen-4-yl) propyl] pentanamide (Preparation 34) (150 mg, 0.28 mmol) was reacted with (R) -1-phenylethylamine (35 μl, 0.28 mmol) at room temperature for 2.5 hours. The mixture was poured into ethyl acetate (75 ml) and washed with 0.5 M aqueous sodium monophosphate (2 x 50 ml) and 5% aqueous sodium hydrogen carbonate (50 ml) (phase separated by addition of solid sodium chloride). The organic solution was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residual oil was purified by flash chromatography (eluting with hexanes: ethyl acetate = 35: 65) to give (2R) -2-[(4S) -2,2-dimethyl-5-oxo-1,3-diox as a white solid. Solan-4-yl] -N-[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl] -5-[(3'-meth Methoxy-2-methylbiphen-4-yl) propyl] pentanamide (133 mg, 76%) was obtained.

R _f 0.49 (hexane: ethyl acetate: acetic acid = 50: 50: 1)

b) (2R) -2-[(4S) -2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl] -N (from above a) according to the method of example 19 -[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl] -5-[(3'-methoxy-2-methylbiphen-4 -Yl) propyl] pentanamide (133 mg, 0.21 mmol) was reacted with hydroxylamine (59 mg, 0.85 mmol) at room temperature for 18 hours. The solution was concentrated under reduced pressure and purified by column chromatography (C ₁₈ silanated silica gel (40-63 μ), eluting with methanol: water = 3: 2 to 4: 1 gradient) and triturated with diisopropyl ether. To give the title compound (57 mg, 45%) as a white solid.

m.p. 98-100 ℃

R _f 0.20 (Dichloromethane: Methanol = 95: 5)

_{C 35 H 45 N 3 O 6} · 0.2H ₂ O Elemental analysis

Found: C, 69.17; H, 7.55; N, 6.87;

Theoretical value: C, 69.22; H, 7.53; N, 6.92%

<Example 31>

(N4, 3S) -dihydroxy-N1-[(1S) -2,2-dimethyl-1-({[(1S) -2-methoxy-1-phenylethyl] amino} carbonyl) propyl]- (2R) -2- {3-[(3'-methoxy-2-methylbiphen-4-yl) propyl} butanediamide

a) Example 25 According to the method of (a), (2R) -N-[(1S) -1- (carboxy) -2,2-dimethylpropyl] -2-[(4S) -2,2-dimethyl -5-oxo-1,3-dioxolan-4-yl] -5-[(3'-methoxy-2-methylbiphen-4-yl) propyl] pentanamide (Preparation 34) (220 mg, 0.42 mmol) was reacted with (1S) -2-methoxy-1-phenylethylamine (63 mg, 0.42 mmol) at room temperature for 2.5 hours. The mixture was poured into ethyl acetate (75 ml) and washed with 0.5 M aqueous sodium monophosphate (2 x 50 ml) and 5% aqueous sodium hydrogen carbonate (50 ml) (phase separated by addition of solid sodium chloride). The organic solution was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane eluting with hexane: ethyl acetate = 30: 70 to 60:40) to give a white solid which was flash chromatography (sorbyl C ₆₀ , (20-40 μ) silica gel, hexane Eluting with ethyl acetate = 35: 65) once more to yield (2R) -2-[(4S) -2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl as a white solid. ] -N-[(1S) -2,2-dimethyl-1-({[(1S) -2-methoxy-1-phenylethyl] amino} carbonyl) propyl] -5-[(3'-meth Methoxy-2-methylbiphen-4-yl) propyl] pentanamide (191 mg, 69%) was obtained.

R _f 0.37 (hexane: ethyl acetate = 1: 1)

b) (2R) -2-[(4S) -2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl] -N (from above a) according to the method of example 19 -[(1S) -2,2-dimethyl-1-({[(1S) -2-methoxy-1-phenylethyl] amino} carbonyl) propyl] -5-[(3'-methoxy-2 -Methylbiphen-4-yl) propyl] pentanamide (191 mg, 0.29 mmol) was reacted with hydroxylamine for 17 hours at room temperature. The solution was concentrated under reduced pressure, purified by column chromatography (C ₁₈ silanated silica gel (40-63 μg), eluting with methanol: water = 60: 40 to 70:30 gradient) and triturated with diisopropyl ether. To give the title compound (81 mg, 44%) as a white solid.

m.p. 82-89 ℃

R _f 0.40 (Dichloromethane: Methanol = 90: 10)

Elemental Analysis of C ₃₆ H ₄₇ N ₃ O ₇ · 0.4H ₂ O

Found: C, 67.47; H, 7.52; N, 6.55;

Theoretical value: C, 67.46; H, 7.52; N, 6.56%

<Example 32>

(2R) -N1-[(1S) -2,2-dimethyl-1-({[(1S) -2-methoxy-1-phenylethyl] amino} carbonyl) propyl]-(N4-hydroxy) -2- {3- [3'-methoxy-2-methylbiphen-4-yl] propyl} butanediamide

a) According to the method of Example 2, (3R) -3-({[(1S) -2,2-dimethyl-{[(1S) -2-methoxy-phenylethyl] amino] carbonyl) propyl] Amino} carbonyl) -6-[(3'-methoxy-2-methylbiphen-4-yl] hexanoic acid (Example 15) (603 mg, 1.0 mmol) was dissolved in O-allylhydroxylamine hydrochloride (134 mg, 1.2 mmol) The crude product was purified by flash chromatography (hexane: ethyl acetate = 1: 1 to 1: 2 gradient eluting) followed by flash chromatography (dichloromethane: methanol: concentrated aqueous ammonia =). Repeated purification with elution to 95: 5: 0.5) as colorless foam as (2R) -N1-[(1S) -2,2-dimethyl-1-({[(1S) -2-methoxy-1-phenylethyl ] Amino} carbonyl) propyl] -2- {3- [3'-methoxy-2-methylbiphen-4-yl] propyl}-(N4-3-propenyloxy) butanediamide (397 mg, 60 %) Was obtained.

m.p. 76-79 ℃

R _f 0.35 (hexane: ethyl acetate = 1: 2)

Elemental Analysis of C ₃₉ H ₅₁ N ₃ O ₆

Found: C, 70.89; H, 7.85; N, 6. 27;

Theoretical value: C, 71.21; H, 7.81; N, 6.39%

b) (2R) -N1-[(1S) -2,2-dimethyl-1-({[(1S) under a palladium catalyst in ethanol / water (4: 1, 10 ml) according to the method of example 2 -2-methoxy-1-phenylethyl] amino} carbonyl) propyl] -2- {3- [3'-methoxy-2-methylbiphen-4-yl] propyl}-(N4-3-propenyl Oxy) butanediamide (380 mg, 0.58 mmol) was reacted with ammonium formate (366 mg, 5.80 mmol) under reflux for 1 hour. After finishing treatment, the residue was purified as a colorless solid by reverse phase flash chromatography (eluting with C ₁₈ silanated silica gel (40-63 μ), methanol: water = 4: 1) to give (2R) -N1-[( 1S) -2,2-dimethyl-1-({[(1S) -2-methoxy-1-phenylethyl] amino} carbonyl) propyl]-(N4-hydroxy) -2- {3- [3 '-Methoxy-2-methylbiphen-4-yl] propyl} butanediamide (260 mg, 73%) was obtained.

m.p. 166-168 ℃

R _f 0.29 (Reverse phase tlc, Methanol: Water = 4: 1)

_{C 36 H 47 N 3 O 6} · 0.5H ₂ O Elemental analysis

Found: C, 69.06; H, 7.80; N, 6.65;

Theoretical: C, 68.99; H, 7.72; N, 6.70%

<Production example 1>

(2S) -amino-3,3-dimethyl-N-[(1R) -1-phenylethyl] butanamide, hydrochloride.

a) tert-butyl N-[(1S) -2,2-dimethyl-1-carboxy) propyl] carbamate (34.7 g, 150 mmol) in anhydrous dichloromethane (350 ml) at 4 ° C. nitrogen (Fluka Chemicals; J. Pospisek, K. Blaha, Coll. Czech.Chem.Commun., 1977, 42, 1069-76]) and 1-hydroxy-1,2,3-benzotriazole hydrate (22.3 g, 165 mmol) To a stirred mixture of) was added N- (dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (35.47 g, 185 mmol). After 1 hour, (R)-(1-phenyl) ethylamine (19.14 g, 158 mmol) was added followed by N-methylmorpholine (16.7 g, 165 mmol). After 30 more minutes, the mixture was allowed to warm to room temperature. After 17 h at rt, the mixture was concentrated under reduced pressure and partitioned between ethyl acetate (400 ml) and water (400 ml). The organic solution was washed sequentially with 5% aqueous citric acid (2 × 400 ml) and saturated aqueous sodium hydrogen carbonate (500 ml) (MgSO ₄ ) and concentrated under reduced pressure. The residue was triturated with diethyl ether, filtered and dried to give (2S) -tert- (butoxycarbonyl) amino-3,3-dimethyl-N-[(1R) -1-phenylethyl] butanamide as a colorless solid. (47.5 g, 94%) was obtained.

m.p. 166-169 2 ℃

R _f 0.7 (hexane: ether: acetic acid = 30: 70: 1)

Elemental Analysis of C ₁₉ H ₃₀ N ₂ O ₃

Found: C, 68.30; H, 9.08; N, 8.39;

Theoretical value: C, 68.23; H, 9.04; N, 8.38%

b) (2S) -tert- (butoxycarbonyl) amino-3,3-dimethyl-N-[(1R) -1-phenylethyl in a mixture of anhydrous dichloromethane (600 ml) and dioxane (150 ml) ] Butanamide (46.4 g, 139 mmol) was dissolved and cooled to 4 ° C. Hydrogen chloride was bubbled through the solution until a saturated solution formed. After stirring at 4 ° C. for 4 hours, the solution was concentrated under reduced pressure. The residue was triturated with ether and filtered to give the title compound (38.0 g, 100%).

R _f 0.46 (hexane: isopropanol: concentrated aqueous ammonia = 80: 20: 1)

Elemental Analysis of C ₁₄ H ₂₂ N ₂ O.HClH ₂ O

Found: C, 61.98; H, 8.71; N, 10.09;

Theoretical value: C, 62.09; H, 8.56; N, 10.34%

<Production example 2>

tert-butyl (3R) -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl] amino} carbonyl) hex- 5-enoate

(2R) -2- [2- (tert-butoxy) -2-oxoethyl] pent-4-enoic acid in anhydrous dimethylformamide (60 ml) at 4 ° C. nitrogen (AL Castelhano, SL Bender, JG Deal, S. Horner, TJ Liak, Z. Yuan, WO 96/16027 (1996)]) (3.80 g, 17.8 mmol) and 1-hydroxy-7-azabenzotriazole (2.49 g, 18.3 mmol) To a stirred mixture of was added N- (dimethylaminopropyl) -N'-ethylcarbodiimide (4.21 g, 22.0 mmol). After 1 hour, (2S) -amino-3,3-dimethyl-N-[(1R) -1-phenylethyl] butanamide hydrochloride (Preparation Example 1) (5.10 g, 18.8 mmol) followed by diisopropylethyl Amine (2.42 g, 19.2 mmol) was added. After 30 minutes more, the mixture was allowed to warm to room temperature. After 17 h at rt, the mixture was concentrated under reduced pressure and partitioned between ethyl acetate (400 ml) and water (400 ml). The aqueous phase was saturated with sodium bicarbonate and extracted with ethyl acetate (2 x 100 ml). The combined organic solutions were concentrated under reduced pressure, and the residue was dissolved in ether (500 ml), washed with water (3 × 200 ml), dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was triturated with pentane, filtered and dried to give tert-butyl (3R) -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl]] as a colorless solid. Amino} carbonyl) propyl] amino} carbonyl) hex-5-enoate (6.70 g, 88%) was obtained.

m.p. 123-126 ℃

R _f 0.16 (hexane: isopropanol = 98: 2)

Elemental Analysis of C ₂₅ H ₃₈ N ₂ O ₄

Found: C, 69.30; H, 8.96; N, 6.54;

Theoretical value: C, 69.74; H, 8. 90; N, 6.51%

<Production example 3>

tert-butyl (3R) -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl] amino} carbonyl) -6 -[3-methyl- (4-phenyl) phenyl] -hexanoate

a) A mixture of palladium acetate (52 mg, 0.23 mmol) and tri- (2-methylphenyl) phosphine (141 mg, 0.46 mmol) in anhydrous acetonitrile (10 ml) was stirred at room temperature for 1 minute until a creamy suspension formed. Sonication was performed at. Tert-butyl (3R) -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl in anhydrous acetonitrile (15 ml) under nitrogen ) Propyl] amino} carbonyl) hex-5-enoate (Preparation Example 2) (861 mg, 2.0 mmol), 3-methyl-4-phenylbromobenzene (M. Gomberg, JC Pernert, J. Amer) This suspension was added to a stirred solution of Chem. Soc., 1926, 48, 1372-84, 1372-84 and Preparation Example 19b) (1.32 mg, 5.34 mmol) and triethylamine (1.28 ml, 9.29 mmol). It was added by Pasteur pipette. The mixture was purged with nitrogen and then heated at reflux for 24 hours. The mixture was poured into ethyl acetate (200 ml), washed with saturated aqueous sodium chloride (2 × 100 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography (dilution with dichloromethane: ethyl acetate) to give tert-butyl (3R, 5E) -3-({[(1S) -2,2-dimethyl-1- () as colorless foam. {[(1R) -1-phenylethyl] amino} carbonyl} propyl] amino} carbonyl) -6- [3-methyl- (4-phenyl) phenyl] hex-5-enoate (1.91 gm, 69% ¹ H NMR shows that two alkene isomers, (5Z) and (4E), are also present A mixture of alkenes is used in the next step (see b below).

R _f 0.52 (Dichloromethane: ethyl acetate = 9: 1)

b) tert-butyl (3R, 5E) -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl in ethanol (80 ml) } Propyl] amino} carbonyl) -6- [3-methyl- (4-phenyl) phenyl] hex-5-enoate (1.91 gm, 3.2 mmol) on charcoal (120 mg) at 3 bar and 20 ° C. The mixture was hydrogenated at 10% palladium for 16 hours The mixture was filtered through an arbocell filtration aid and concentrated under reduced pressure to afford tert-butyl (3R) -3-({[(1S) -2,2-dimethyl- as colorless foam. 1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl] amino} carbonyl) -6- [3-methyl- (4-phenyl) phenyl] hexanoate (2.07 gm, 108% ) Was used in the next step without purification (see Example 1).

R _f 0.52 (Dichloromethane: ethyl acetate = 9: 1)

Elemental Analysis of C ₃₈ H ₅₀ N ₂ O ₄

Found: C, 75.86; H, 8. 44; N, 4.60;

Theoretical value: C, 76.22; H, 8.42; N, 4.68%

<Example 33 / Production Example 4>

(3R) -6-[(3-chloro-4-phenyl) phenyl] -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} Carbonyl) propyl] amino} carbonyl) hexanoic acid

a) A mixture of palladium acetate (24 mg, 0.1 mmol) and tri- (2-methylphenyl) phosphine (61 mg, 0.2 mmol) in anhydrous acetonitrile (1 ml) was stirred at room temperature for 1 minute until a creamy suspension formed. Sonication was performed at. Tert-butyl (3R) -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl in anhydrous acetonitrile (3 ml) under nitrogen ) Propyl] amino} carbonyl) hex-5-enoate (Preparation 2) (861 mg, 2.0 mmol), (3-chloro-4-phenyl) phenyl trifluoromethanesulfonate (Preparation 9) (740 mg, 2.2 mmol) and triethylamine (420 μL, 3.0 mmol) were added by Pasteur pipette to this suspension. The mixture was purged with nitrogen and then heated at reflux for 22 hours. Also (3-chloro-4-phenyl) phenyl trifluoromethanesulfonate (200 mg, 0.59 mmol, triethylamine (420 μl, 3.0 mmol), palladium acetate (35 mg, 0.145 mmol) and tri- (2- Reagents such as methylphenyl) phosphine (89 mg, 0.29 mmol) and a certain amount of catalyst were added and further heated for 8 hours The mixture was poured into ethyl acetate (100 ml) and washed with saturated aqueous sodium chloride (2 x 50 ml) And dried under reduced pressure (MgSO ₄ ) The residue was purified by flash chromatography (eluting with toluene: ethyl acetate = 9: 1) to give colorless foam mainly tert-butyl (3R, 5E) -6- [3. -Chloro- (4-phenyl) phenyl] -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl} propyl] amino} carbon Bonyl) hex-5-enoate (936 mg, 76%) ¹ H NMR shows that there are also two alkene isomers, (5Z) and (4E). Used (see b below).

R _f 0.14 (toluene: ethyl acetate = 10: 1)

b) tert-butyl (3R, 5E) -6- [3-chloro- (4-phenyl) phenyl] -3-({[(1S) -2,2-dimethyl-1 in toluene (15 ml) under nitrogen -({[(1R) -1-phenylethyl] amino} carbonyl} propyl] amino} carbonyl) hex-5-enoate (936 mg, 1.52 mmol) and p-toluenesulfonyl hydrazide (1.41 gm, 7.60 mmol) was stirred under reflux for 4 h After cooling, the mixture was diluted with ether (150 ml), water (50 ml), 0.5 M hydrochloric acid (50 ml) and saturated aqueous sodium chloride (50 ml). ), Dried (MgSO ₄ ) and concentrated under reduced pressure The residue was purified by flash chromatography (elution with hexanes / ethyl acetate) to give tert-butyl (3R) -6- [3- as a colorless foam. Chloro- (4-phenyl) phenyl] -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl] amino} carbonyl Hexanoate (701 mg, 74%) was obtained.

R _f 0.36 (hexane: ethyl acetate = 5: 1)

c) tert-butyl (3R) -6- [3-chloro- (4-phenyl) phenyl] -3-({[(1S) -2,2-dimethyl-1- () in dioxane anhydride (30 ml) {[(1R) -1-phenylethyl] amino} carbonyl) propyl] amino} carbonyl) hexanoate (655 mg, 1.07 mmol) was dissolved and cooled in an ice water bath under nitrogen. Hydrogen chloride gas was bubbled through the stirred solution for 15 minutes until the solution was saturated. The solution was stirred for 3 hours and then concentrated under reduced pressure. The residue was dissolved in toluene and concentrated three times under reduced pressure to add hexane and ethyl acetate to give a crystallized colorless rubber. The white solid was recrystallized from ethyl acetate / diisopropyl ether to give the title compound (325 mg, 54%).

m.p. 154-155.5 ° C (from ethyl acetate / diisopropyl ether)

R _f 0.38 (ether: hexane: acetic acid = 70: 30: 1)

Elemental Analysis of C ₃₃ H ₃₉ ClN ₂ O ₄

Found: C, 70.29; H, 6.98; N, 4.91;

Theoretical value: C, 70.38; H, 6.98; N, 4.97%

<Example 34 / Production Example 5>

(3R) -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl] amino} carbonyl) -6- (3 -Fluoro-4-phenoxyphenyl) hexanoic acid

a) tert-butyl (3R) -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} in anhydrous acetonitrile (3 ml) under nitrogen) Carbonyl) propyl] amino} carbonyl) hex-5-enoate (Preparation 2) (700 mg, 1.63 mmol), 3-fluoro-4-phenoxy-bromobenzene (Preparation 10) (479 mg , 1.79 mmol) and a mixture of palladium acetate (20 mg, 0.08 mmol) and tri- (2-methylphenyl) phosphine (50 mg, 0.16 mmol) were added to a stirred solution of triethylamine (340 μl, 2.43 mmol). . The mixture was purged with nitrogen and then heated at reflux for 14 hours. Further palladium acetate (20 mg, 0.08 mmol) and tri (2-methylphenyl) phosphine (50 mg, 0.16 mmol) were added and the mixture was further heated for 9 hours. After cooling, the mixture was poured into ethyl acetate (100 ml), washed with saturated aqueous sodium chloride (2 x 50 ml), dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with hexanes: ethyl acetate = 9: 1) to give tert-butyl (3R, 5E) -3-({[(1S) -2,2-dimethyl-1 as colorless oil. -({[(1R) -1-phenylethyl] amino} carbonyl} propyl] amino} carbonyl) -6- [3-fluoro-4-phenoxyphenyl) hex-5-enoate (949 mg) Got. ¹ H NMR shows that two alkene isomers, (5Z) and (4E), are also present with the alkene starting material (10%). A mixture of alkenes was used for the next step (see b below).

R _f 0.24 (hexane: ethyl acetate = 3: 1)

b) tert-butyl (3R) -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl} propyl in methanol (10 ml) ] Amino} carbonyl) -6- [3-fluoro-4-phenoxyphenyl) hexanoate (949 mg, 1.53 mmol), ammonium formate (474 mg, 7.51 mmol) and 10 on charcoal (100 mg) The solution of% palladium was stirred at 20 ° C for 16 h. This mixture was filtered through an arbocell filtration aid and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium chloride, dried (MgSO ₄ ) and concentrated under reduced pressure to afford tert-butyl (3R) -3-({[(1S) -2,2-dimethyl-1 as a colorless foam -({[(1R) -1-phenylethyl] amino} carbonyl) propyl] amino} carbonyl) -6- [3-fluoro-4-phenoxyphenyl) hexanoate (876 mg, 92%) Was obtained and used in the next step without purification.

R _f 0.29 (hexane: ethyl acetate = 3: 1)

c) tert-butyl (3R) -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl]] in anhydrous dichloromethane (6 ml) at 20 ° C. nitrogen. To a stirred solution of amino} carbonyl) propyl] amino} carbonyl) -6- (3-fluoro-4-phenoxyphenyl) hexanoate (876 mg, 1.41 mmol) was added trifluoroacetic acid (2 ml). Dropwise over 5 minutes. The solution was stirred for 16 hours and concentrated under reduced pressure. The residue was dissolved in toluene and concentrated under reduced pressure (twice). Purification by flash chromatography (eluting with hexanes: ethyl acetate: acetic acid = 75: 25: 1) gave the title compound as a yellow gum (784 mg, 98%).

R _f 0.21 (hexane: ethyl acetate: acetic acid = 75: 25: 1)

<Example 35 / Production Example 6>

(3R) -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl] amino} carbonyl) -6- (3 -Methyl-4-phenoxyphenyl) hexanoic acid

a) tert-butyl (3R) -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} in anhydrous acetonitrile (3 ml) under nitrogen) Carbonyl) propyl] amino} carbonyl) hex-5-enoate (Preparation 2) (578 mg, 1.23 mmol), 1-iodo-3-methyl-4-phenoxybenzene (Preparation 11) (384 mg, 1.35 mmol) and a mixture of palladium acetate (20 mg, 0.08 mmol) and tri- (2-methylphenyl) phosphine (50 mg, 0.16 mmol) were added to a stirred solution of triethylamine (300 μl, 2.14 mmol). It was. The mixture was purged with nitrogen and then heated at reflux for 24 hours. After cooling, the mixture was poured into ethyl acetate (100 ml), washed with saturated aqueous sodium chloride (2 x 50 ml), dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane: ethyl acetate = 9: 1 followed by 4: 1) to give tert-butyl (3R, 5E) -3-({[(1S) -2, 2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl} propyl] amino} carbonyl) -6- (3-methyl-4-phenoxyphenyl) hex-5-enoate (615 mg) ¹ H NMR shows that two alkene isomers, (5Z) and (4E), are also present with the alkene starting material (10%) A mixture of alkenes was used in the next step (below) b).

R _f 0.5 (hexane: ethyl acetate = 3: 1)

b) tert-butyl (3R, 5E) -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl in methanol (8 ml) } Propyl] amino} carbonyl) -6- (3-methyl-4-phenoxyphenyl) hex-5-enoate (615 mg, 1.00 mmol), ammonium formate (310 mg, 4.9 mmol) and charcoal (65 mg) solution of 10% palladium on 16 ° C. was stirred for 16 h at 20 ° C. The mixture was filtered through an arbocell filtration aid and concentrated under reduced pressure The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium chloride and dried (MgSO ₄ ) Concentrated under reduced pressure to form tert-butyl (3R) -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl as a foam ) Propyl] amino} carbonyl) -6- [3-methyl-4-phenoxyphenyl) hexanoate (550 mg, 90%) was obtained, which was used in the next step without purification.

R _f 0.5 (hexane: ethyl acetate = 3: 1)

c) tert-butyl (3R) -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl]] in anhydrous dichloromethane (5 ml) at 20 ° C. nitrogen. To a stirred solution of amino} carbonyl) propyl] amino} carbonyl) -6- (3-methyl-4-phenoxyphenyl) hexanoate (550 mg, 0.9 mmol) was added 5 ml of trifluoroacetic acid (2.5 ml). Dropwise added over minutes. The solution was stirred for 1 hour and concentrated under reduced pressure. The residue was diluted with hydrochloric acid (2M) and extracted three times with ethyl acetate. The combined organic solution was washed with saturated aqueous sodium chloride, dried (MgSO ₄ ) and concentrated under reduced pressure. Toluene was added in two portions and evaporated to afford the title compound contaminated with toluene and trifluoroacetic acid as a yellow gum (640 mg).

R _f 0.18 (dichloromethane: methanol = 99: 1)

<Production example 7>

Methyl (2S, 3R) -3-carboxy-2-ethoxy-hex-4-enoate

a) n-butyllithium (23.0 ml, 2.5 M in hexane, 57.5 mmol) was added dropwise to a stirred solution of diisopropylamine (9.63 ml, 69.0 mmol) in anhydrous tetrahydrofuran (10 ml) under -78 ° C nitrogen. . The reaction flask was placed in an ice water bath for 10 minutes and then recooled to -78 ° C. After adding anhydrous tetrahydrofuran (10 ml), a solution of (S) -diisopropyl malate (6.0 gm, 27.0 mmol) in anhydrous tetrahydrofuran (20 ml) was added dropwise. The mixture was warmed to -20 ° C and stirred for 8 hours. The mixture was then recooled to -78 ° C and freshly distilled allyl iodide (2.75 ml, 30 mmol) was added dropwise. This mixture was warmed to -40 ° C and stirred for 36 h. This mixture was poured into ice cold 5% aqueous citric acid (150 ml) and extracted with ethyl acetate (3 × 150 ml). The combined organic solution was washed with saturated aqueous sodium chloride, dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with hexanes: ethyl acetate = 80: 20) to give (2S, 3R)-and (2S, 3S) -isopropyl 2-hydroxy-3- (2- as light yellow oils. A mixture of propyloxycarbonyl) -5-hexenoate (5.42 gm, 76%) (14: 1) was obtained.

R _f 0.63 (hexane: ethyl acetate = 1: 1)

b) (2S, 3R)-and (2S, 3S) -isopropyl 2-hydroxy-3- (2-propyloxycarbonyl) -5-hexenoate and 2,6-di-tert-butyl-4 To a mixture of -methylpyridine (2.88 g, 14.0 mmol) (1.45 gm, 5.6 mmol) (14: 1) is added ethyl trifluoromethanesulfone (1.45 ml, 11.2 mmol) and the mixture at 45 <0> C under nitrogen. Stir for 5.5 h, 18 h at 20 ° C and 24 h at 45 ° C. The cold mixture was applied on top of a single column of silica gel and eluted with ethyl acetate. The filtrate was concentrated under reduced pressure and purified by flash chromatography (hexane: ethyl acetate = 85: 15) to give (2S, 3R) -isopropyl 2-ethoxy-3- (2-propyloxycarbonyl) -5-hexeno. Obtained (627 mg, 39%).

R _f 0.62 (hexane: ethyl acetate = 70: 30)

c) Methanol: (1S, 3R) -isopropyl 2-ethoxy-3- (2-propyloxycarbonyl) -5-hexenoate (500 mg, 1.75 mmol) in water = 1: 1 (6 ml) And a mixture of lithium hydroxide hydrate (154 mg, 3.67 mmol) were stirred under room temperature nitrogen for 22 hours and then concentrated under reduced pressure. Since NMR showed incomplete reaction, more lithium hydroxide hydrate (154 mg, 3.67 mmol) and methanol: water = 1: 1 (6 ml) were added and the mixture was stirred at 50 ° C. for 20 hours. The mixture was cooled and concentrated under reduced pressure, toluene was added and evaporated several times. The residue was dried in sodium hydroxide pellets in vacuo and used in the next step without purification.

d) stirring of dilithium (2S, 3R) -2-ethoxy-3- (prop-3-enyl) butanedioate (393 mg from c above) in anhydrous tetrahydrofuran (2.6 ml) at 0 ° C. nitrogen. Trifluoroacetic anhydride (2.62 ml) was added dropwise to the suspension. The mixture was stirred for 4 hours and concentrated under reduced pressure. Toluene was added and evaporated several times. The resulting rubber was dissolved in 0 ° C. anhydrous methanol (2 ml) and warmed to room temperature overnight. The solution was concentrated under reduced pressure and then the residue was partitioned between saturated aqueous sodium citrate and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined organic solution was washed with saturated aqueous sodium chloride, dried (NaSO ₄ ) and concentrated under reduced pressure to afford the title compound as pale yellow oil (220 mg). Many of the impurities are evident by ¹ H NMR, which may be the (2S, 3S) isomer.

R _f 0.3 (dichloromethane: methanol: acetic acid = 95: 5: 1)

<Example 36 / Production Example 8>

(2S, 3R) -3-([(1S) -2,2-dimethyl-1-({(1R) -1-phenylethyl] aminocarbonyl) propyl] aminocarbonyl) -2-ethoxy-6 -(3-fluoro-4-phenoxyphenyl) hexanoic acid

a) methyl (2S, 3R) -3-carboxy-2-ethoxy-hex-4-enoate (Preparation Example 7) (210 mg, 0.97 mmol) in anhydrous dimethylformamide (4 ml) at 0 ° C. nitrogen; To a stirred mixture of 1-hydroxy-7-azabenzotriazole (139 mg, 1.02 mmol) was added N- (dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (214 mg, 1.12 mmol). After 1 hour (2S) -amino-3,3-dimethyl-N-[(1R) -1-phenylethyl] butanamide hydrochloride (Preparation Example 1) (276 mg, 1.02 mmol) followed by diisopropylethylamine (0.18 μl, 1.02 mmol) was added. After 30 more minutes, the mixture was allowed to warm to room temperature. After 17 h at rt, the mixture was concentrated under reduced pressure and partitioned between ethyl acetate (50 ml) and water (50 ml). The aqueous layer was saturated with sodium bicarbonate and extracted with ethyl acetate (2 x 20 ml). The combined organic solutions were concentrated under reduced pressure, dissolved in ether (50 ml), washed with water (3 × 20 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with hexanes: ethyl acetate = 60: 40) to give (2S, 3R) -3-({[(1S) -2,2-dimethyl-1-({[ (1R) -1-Fenylethyl] amino} carbonyl) -2-ethoxy-hex-5-enoate (181 mg, 43%) (found as single diastereomer by ¹ H NMR) was obtained.

m.p. 131-134 ℃

R _f 0.4 (hexane: ethyl acetate = 1: 1)

b) A mixture of palladium acetate (12 mg, 0.05 mmol) and tri- (2-methylphenyl) phosphine (30 mg, 0.10 mmol) in anhydrous acetonitrile (1 ml) was stirred at room temperature for 1 minute until a creamy suspension formed. Sonication was performed at. (2S, 3R) -3-([(1S) -2,2-dimethyl-1-({(1R) -1-phenylethyl] amino} carbonyl) propyl] in anhydrous acetonitrile (1 ml) under nitrogen Amino} carbonyl) -2-ethoxy-hex-5-enoate (415 mg, 0.96 mmol), 3-fluoro-4-phenoxy-bromobenzene (Preparation 10) (400 mg, 1.50 mmol) And to a stirred solution of triethylamine (280 μl, 2.0 mmol) with a Pasteur pipette. The mixture was purged with nitrogen and then heated at reflux for 16 hours. After cooling, the mixture was poured into ethyl acetate (70 ml), washed with 5% aqueous citric acid (20 ml), saturated aqueous sodium chloride (50 ml), dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with dichloromethane: ethyl acetate) to give methyl (2S, 3R, 5E) -3-({[(1S) -2,2-dimethyl-1- () as a light yellow foam. {[(1R) -1-phenylethyl] amino} carbonyl} propyl] amino} carbonyl) -2-ethoxy-6- (3-fluoro-4-phenoxyphenyl) hex-5-enoate ( 359 mg, 69%) ¹ H NMR shows that there are also two alkene isomers, (5Z) and (4E) A mixture of alkenes was used for the next step (see c below).

R _f 0.36 (Dichloromethane: ethyl acetate = 10: 1)

c) methyl (2S, 3R, 5E) -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl in ethanol (15 ml) } Propyl] amino} carbonyl) -2-ethoxy-6- (3-fluoro-4-phenoxyphenyl) hex-5-enoate (350 mg, 0.566 mmol) at 3 bar and 20 ° C. Hydrogenated at 10% palladium on charcoal (60 mg) for 16 hours The mixture was filtered through an arbocell filtration aid and concentrated under reduced pressure The residue was dissolved in cyclohexane and evaporated (twice) as a colorless foam. Methyl (2R, 3R) -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl] amino} carbonyl) -2 -Ethoxy-6- (3-fluoro-4-phenoxyphenyl) hexanoate (368 mg, 105%) was obtained, which was used in the next step without purification.

R _f 0.29 (hexane: ethyl acetate = 2: 1)

d) Methanol: Water = methyl (2S, 3R) -3-({[1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino in 10: 1 (5 ml) Lithium hydroxide hydrate (116 mg) in a solution of} carbonyl) propyl] amino} carbonyl) -2-ethoxy-6- (3-fluoro-4-phenoxyphenyl) hexanoate (368 mg, 0.566 mmol) 2.83 mmol) was added and the mixture was stirred at room temperature for 2 hours. This solution was neutralized with 5% aqueous citric acid and concentrated under reduced pressure. The residue was partitioned between ethyl acetate (100 ml) and 5% aqueous citric acid (20 ml), washed with saturated aqueous sodium chloride (20 ml), dried (MgSO ₄ ) and concentrated under reduced pressure. Purification by flash chromatography (eluting with dichloromethane: methanol = 20: 1 to 10: 1) gave the title compound (62 mg, 18%) and some mixed fractions as a colorless glass. These were combined and re-purified by flash chromatography (eluting with ethyl acetate: hexane: acetic acid = 33: 66: 1 to 50: 50: 1) to give the title compound (37 mg, 11%) as a white solid.

m.p. 185-187 ℃

R _f 0.23 (ether: hexane: acetic acid = 70: 30: 1)

<Production example 9>

(3-chloro-4-phenyl) phenyl trifluoromethanesulfonate

Trifluoro in a stirred solution of (3-chloro-4-phenyl) phenol (759 mg, 3.71 mmol) (International Patent No. 97/20815) and anhydrous pyridine (785 μL, 9.65 mmol) in anhydrous dichloromethane at 0 ° C. nitrogen. Rhomethanesulfonic anhydride (755 μl, 4.45 mmol) was added dropwise over 2 minutes. The mixture was stirred at 0 ° C. for 1.5 hours and then at 20 ° C. for 2.5 hours. The mixture was poured into a mixture of ether / hexanes (200 ml, 50:50) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography (eluting with hexanes: ether = 20: 1) to give the title compound (1062 mg, 85%) as a colorless oil which was left to stand at room temperature for several days. Crystallized.

<Production example 10>

3-fluoro-4-phenoxy-bromobenzene

Aqueous sodium hydroxide (5.5 ml, 1M, 5.5) in a mixture of 4-bromo-2-fluorophenol (0.96 gm, 5.0 mmol) and diphenyliodonium bromide (1.99 gm, 5.5 mmol) in water (20 ml) mmol) was added and the mixture was heated at reflux for 4 h. After cooling, the reaction mixture was diluted with ether and filtered. The organic phase was washed with saturated aqueous sodium chloride, dried (MgSO ₄ ) and concentrated under reduced pressure. The remaining dark orange oil was purified by flash chromatography (eluting with hexanes) to give the title compound (1.2 gm, 90%) as an orange oil.

<Production example 11>

1-iodo-3-methyl-4-phenoxybenzene

Aqueous sodium hydroxide (33 ml, 1M, 33 mmol) in a mixture of 4-iodo-2-methylphenol (7.0 gm, 29.9 mmol) and diphenyliodonium bromide (11.89 gm, 32.9 mmol) in water (120 ml) ) Was added and the mixture was heated at reflux for 4 h. After cooling, the mixture was extracted with ethyl acetate (4 × 100 ml), and the combined extracts were washed with saturated aqueous sodium chloride, dried (MgSO ₄ ) and concentrated under reduced pressure. The remaining dark orange oil was repeatedly purified by flash chromatography (first eluting with hexanes, then with pentane) to give the title compound (7.84 gm, 84%) as an orange oil.

<Production example 12>

tert-butyl (2S, 3R) -3-carboxy-2-propyl-hex-5-enoate

a) n-butyllithium (2.2 ml, 2.5 M in hexanes, 5.6 mmol) was added to a stirred solution of diisopropylamine (0.73 ml, 5.6 mmol) in anhydrous tetrahydrofuran (3 ml) under -5 ° C nitrogen. . After 1 hour the solution was cooled to -70 ° C and N, N'-dimethylpropyleneurea (DMPU) (3 ml) was added. Then (2R) -2- [2- (tert-butoxy) -2-oxoethyl] pent-4-enoic acid (535 mg, in anhydrous tetrahydrofuran (6 ml) while maintaining the reaction temperature at -70 ° C 2.5 mmol) was added dropwise over 15 minutes. After stirring for 1 hour, 1-iodopropane (680 mg, 4.0 mmol) is added dropwise and the mixture is stirred for 1 hour at -70 ° C and then for 2 hours at -40 ° C, and finally warmed to 0 ° C. It was. Methanol (1 ml) was added and the mixture was partitioned between 5% aqueous citric acid (150 ml) and ether (200 ml). The organic layer was washed with 5% aqueous citric acid (75 ml), water (3 × 200 ml), dried (MgSO ₄ ) and concentrated under reduced pressure to give a pale yellow oil. Purified by flash chromatography (eluting with hexanes: ethyl acetate: acetic acid = 80: 20: 2) to give (2R, 3R)-and (2R, 3S) -3- [as colorless oils with a diastereomeric ratio 97: 3. (2-methylprop-2-yl) oxycarbonyl] -2- (3-propen-1-yl) hexanoic acid (472 mg, 74%) was obtained.

R _f 0.31 (hexane: ethyl acetate: acetic acid = 80: 20: 2)

b) (2R, 3R)-and (2R, 3S) -3-[(2-methylprop-2-yl) oxycarbonyl] -2 (from a) above in anhydrous tetrahydrofuran (35 ml) Dissolve a mixture of-(3-propen-1-yl) hexanoic acid (97: 3) (3.05 g, 11.9 mmol) and (n-butyllithium (19.2 ml, 2.5 M in hexane, 48 at -70 ° C) mmol) and a stirred solution of lithium diisopropylamide in anhydrous tetrahydrofuran (25 ml) from diisopropylamine (7.0 ml, 50 mmol) dropwise over 30 minutes. The mixture was warmed to -10 ° C, stirred for 30 minutes, and warmed to 0 ° C for 2 hours. The solution was then cooled to -70 ° C and methanol (15 ml) was quickly added by syringe. This mixture was warmed to room temperature and partitioned between 5% aqueous citric acid (150 ml) and ether (200 ml). The organic layer was washed with 5% aqueous citric acid (50 ml), water (3 × 200 ml), dried (MgSO ₄ ) and concentrated under reduced pressure to give a pale yellow oil. Purified by flash chromatography (hexane eluted with ethyl acetate: acetic acid), a colorless oil with a diastereomeric ratio of 58:42 (2R, 3S)-and (2R, 3R) -3-[(2-methylpro P-2-yl) oxycarbonyl] -2- (3-propen-1-yl) hexanoic acid (3.05 g, 100%) was obtained.

R _f 0.31 (hexane: ethyl acetate: acetic acid = 80: 20: 2)

The stereochemistry for the two isomers is listed below. (2R, 3S)-and (2R, 3R) -3-[(2-methylprop-2-yl) oxycarbonyl] -2- (3-propen-1-yl) hexanoic acid (ratio in ethanol) 1: 3) was hydrogenated at 10% palladium on charcoal (3 bar) and then treated with hydrogen chloride in dry dichloromethane / dioxane (4 ° C., 4 h), Bull. Chem. Soc. (France) 1975, 2189, to obtain (2R, 3S)-and (2R, 3R) -2,3-diprop-1-ylbutanediionic acid (ratio 1: 3). Testing of quantum NMR spectra (acetone-d ₆ ) showed δ _H 2.70 (2H, m, CHCO ₂ H, major isomers) and δ _H 2.55 (2H, m, CHCO ₂ H, isomers).

c) (2R, 3S)-and (2R, 3R) -3-[(2-methylprop-2-yl) oxycarbonyl] -2- (in water (35 ml) and acetonitrile (90 ml) A solution of 3-propen-1-yl) hexanoic acid (3.04 g, 11.9 mmol) (diastereomeric ratio 58:42) and cesium hydrogen carbonate (2.30 g, 11.9 mmol) was stirred at 20 ° C. for 5 minutes. . This solution was evaporated under reduced pressure, the residue dissolved and four times blown from toluene. The resulting rubber was dried under high vacuum for 30 minutes and then dissolved in anhydrous N, N-dimethylacetamide (50 ml). Iodomethane (3.41 g, 24 mmol) was added and the solution was stirred at 20 ° C for 17 h. This solution was concentrated under reduced pressure and partitioned between ether (250 ml) and water (250 ml). The organic layer was washed with water (3 × 200 ml), dried (MgSO ₄ ) and concentrated under reduced pressure to afford (2R, 3S)-and (2R, 3R) -3-[(2-methylprop-2- as yellow oil). Yl) oxycarbonyl] -2- (3-propen-1-yl) hexanoate (3.0 g, 94%) was obtained. TLC (pentane: ether = 10: 1) shows the points of the two products, R _f 0.41 and 0.30.

d) methyl (2R, 3S)-and (2R, 3R) -3-[(2-methylprop-2-yl) oxycarbonyl] -2- (3-propen-1-yl from c) The compound of hexanoate was separated by flash chromatography (pentane: ether = 20: 1 then 10: 1) to give two fractions. The first eluted product was colorless oil, methyl (2R, 3S) -3-[(2-methylprop-2-yl) oxycarbonyl] -2- (3-propen-1-yl) hexanoate ( 1.78 g, 56%, R _f 0.41 (pentane: ether = 10: 1)).

Elemental Analysis of C ₁₅ H ₂₆ O ₄

Found: C, 66.61; H, 9.77;

Theoretical value: C, 66.64; H, 9.69%

The second eluted product was colorless oil, methyl (2R, 3R) -3-[(2-methylprop-2-yl) oxycarbonyl] -2- (3-propen-1-yl) hexanoate ( 760 mg, 24%, R _f 0.30 (pentane: ether = 10: 1)).

Elemental Analysis of C ₁₅ H ₂₆ O ₄

Found: C, 66.70; H, 9.81;

Theoretical value: C, 66.64; H, 9.69%

e) (2R, 3S) -3-[(2-methylprop-2-yl) oxycarbonyl] -2- (3-propen-1-yl) hexano in anhydrous pyridine (50 ml) under nitrogen Eate (1.49 g, 5.51 mmol) and anhydrous lithium iodide (11 g, 82 mmol) were heated at reflux for 17 hours. After cooling, the mixture was poured into 20% aqueous citric acid (500 ml) and extracted with ethyl acetate (250 ml). The organic layer was washed with 5% aqueous citric acid (2 × 150 ml), water (3 × 250 ml), dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was triturated with hexanes, filtered and the filtrate was concentrated under reduced pressure. The crude product was repeatedly purified by flash chromatography (first column eluting with hexanes: ethyl acetate: acetic acid in gradient) to give (2R, 3S) -3-[(2-methylprop-2-yl) oxycarbonyl as colorless oil. ] -2- (3-propen-1-yl) hexanoic acid (788 mg, 56%) was obtained.

R _f 0.3 (hexane: ethyl acetate: acetic acid = 80: 20: 2)

Elemental Analysis of C ₁₄ H ₂₄ O ₄

Found: C, 65.30; H, 9. 44;

Theoretical value: C, 65.60; H, 9.44%

<Production example 13>

tert-butyl (3R) -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl] amino} carbonyl) -6 -[3-Methyl- (4-phenyl) phenyl]-(2S) -propylhexanoate

a) According to the method of Preparation Example 2, (2R, 3S) -3-[(2-methylprop-2-yl) oxycarbonyl] -2- (3-propen-1-yl) hexanoic acid ( 380 mg, 1.48 mmol) (2S) -amino-3,3-dimethyl-N-[(1R) -1-phenylethyl] butanamide hydrochloride (Preparation Example 1) (441 mg, 1.62 mmol) at 4 ° C. The reaction was carried out for 1 hour at and followed by 72 hours at 20 ° C. This mixture was concentrated under reduced pressure and partitioned between ethyl acetate (100 ml) and water (100 ml). The aqueous layer was saturated with sodium bicarbonate and extracted with ethyl acetate (2 x 100 ml). The combined organic solutions were concentrated under reduced pressure, and the residue was dissolved in ether (500 ml), washed with water (3 × 200 ml), dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was triturated with pentane, filtered and dried to give tert-butyl (2S, 3R) -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenyl) as colorless solid. Ethyl] amino} carbonyl) propyl] amino} carbonyl) -2- (1-propyl) hex-5-enoate (579 mg, 80%).

m.p. 180-183 ℃

Elemental Analysis of C ₂₈ H ₄₄ N ₂ O ₄

Found: C, 71.09; H, 9. 46; N, 6. 10;

Theoretical value: C, 71.15; H, 9.38; N, 5.93%

b) tert-butyl (2S, 3R) -3-({[(1S) -2,2) under a palladium catalyst in anhydrous acetonitrile and dimethylformamide (2: 5, 7 ml) according to the method of Preparation Example 3 -Dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl] amino} carbonyl) -2- (1-propyl) hex-5-enoate (543 mg, 1.15 mmol) 3-methyl-4-phenylbromobenzene (356 mg, 1.44 mmol) was reacted at 90 ° C. for 17 hours. The mixture was concentrated under reduced pressure, poured into ethyl acetate (100 ml), washed with water (2 × 100 ml), dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography (elution with hexane: ethyl acetate) to give tert-butyl (2S, 3R, 5E) -3-({[(1S) -2,2-dimethyl-1- as colorless rubber). ({[(1R) -1-phenylethyl] amino} carbonyl} propyl] amino} carbonyl) -6- [3-methyl- (4-phenyl) phenyl] -2- (1-propyl) hex-5 -Enoate (460 mg, 63%) ¹ H NMR shows that there are also two alkene isomers, (5Z) and (4E) A mixture of alkenes was used for the next step (c below) Reference).

c) tert-butyl (2S, 3R, 5E) -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} in ethanol (50 ml) Carbonyl} propyl] amino} carbonyl) -6- [3-methyl- (4-phenyl) phenyl] -2- (1-propyl) hex-5-enoate (437 mg, 0.68 mmol) in 3 bar and Hydrogenated at 10% palladium over charcoal (50 mg) for 17 hours at 20 ° C. The mixture was filtered through an arbocell filtration aid and concentrated under reduced pressure Purification by flash chromatography (hexane eluting with hexane: ethyl acetate). Tert- (2S, 3R) -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl] amino} as a colorless foam Carbonyl) -6- [3-methyl- (4-phenyl) phenyl] -2- (1-propyl) hexanoate (395 mg, 62%) was obtained.

R _f 0.38 (hexane: ethyl acetate = 3: 1)

Elemental Analysis of C ₄₁ H ₅₆ N ₂ O ₄

Found: C, 76.71; H, 8.97; N, 4.35;

Theoretical: C, 76.84; H, 8.81; N, 4.37%

<Production example 14>

(2R) -2-[(4S) -2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl] -N-[(1S) -2,2-dimethyl-1-({ [(1R) -1-phenylethyl] amino} carbonyl) propyl] pent-4-enamide

a) isopropyl (2S, 3R)-and (2S, 3S) -2-hydroxy-3- (2-propyloxycarbonyl)-in dioxane: water (50 ml, 5: 2) at 90 ° C. nitrogen A mixture of 5-hexanoate (6.28 gm, 24.3 mmol) (isomer ratio = 14: 1) (Preparation Example 7, step a) and potassium hydroxide (4.09 g, 72.9 mmol) was heated for 18 hours. The mixture was cooled, diluted with water (200 ml) and passed through an ion exchange column (Dowex 50X8, 300 g) until eluted with no further dilution with water. The eluate was concentrated and dissolved under reduced pressure, evaporated from ethanol (2 times) followed by ether (2 times), and then dried under vacuum to yield (2S, 3R) -2-hydroxy-3 as the main component of the 8: 1 mixture of isomers. -(Prop-3-en-1-yl) butanedioic acid (wax yellow solid, 4.85 g, greater than 100%, including ethanol and ether) was obtained and used directly in the next step without purification.

b) To a mixture of dimethylformamide (36 ml) and 2,2-dimethoxypropane (133 ml) at room temperature the crude diacid was dissolved from a) above and p-toluenesulfonic acid hydrate (231 mg) was added. This mixture was heated at 30 ° C. for 2.5 days. The solvent was removed under reduced pressure to form (4S) -4-[(1R) -1-carboxy-but-3-enyl] -2,2-dimethyl-1,3-diox with dimethylformamide and p-toluenesulfonic acid. 7.5 g of oil containing Solan-5-one as a main component was obtained.

c) Crude (4S) -4-[(1R) -1-carboxy-but-3-enyl] -2,2-dimethyl-1,3-dioxolane from b) above in anhydrous dichloromethane (30 ml) -5-one (1.54 g, calculated by NMR as 7.19 mmol) and a portion of 1-hydroxy-7-aza-1H-1,2,3-benzotriazole (1.09 g, 7.55 mmol) were mixed and Cooled under 0 ° C. nitrogen. N- (dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (1.60 g, 8.27 mmol) was added and the mixture was stirred at 0 ° C for 1.5 h. (2S) -amino-3,3-dimethyl-N-[(1R) -1-phenylethyl] butylamide hydrochloride (Preparation 1) (2.15 g, 7.55 mmol) followed by diisopropylethylamine (1.37 ml , 7.55 mmol) was added. After 45 minutes more, the mixture was allowed to warm to room temperature. After 3 hours at room temperature the mixture was partitioned between ethyl acetate (200 ml) and pH 7 aqueous phosphate buffer (100 ml). The organic layer was saturated with sodium bicarbonate, brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The foam obtained by the addition of ether was crystallized and the white solid (1.89 g) was filtered off. Recrystallized from ethyl acetate / hexanes to give (2S) -2-[(4S) -2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl] -N-[(1S)-as a white solid. 2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl] pent-4-enamide (1.30 g, 42%, single diastereomer) was obtained.

<Production example 15>

(2R) -2-[(4S) -2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl] -N-[(1S) -2,2-dimethyl-1-({ [(1R) -1-phenylethyl] amino} carbonyl) propyl] -5-[(3-fluoro-4-phenoxy) phenyl] pentanamide

a) A mixture of palladium acetate (17 mg, 0.075 mmol) and tri- (2-methylphenyl) phosphine (46 mg, 0.15 mmol) in anhydrous acetonitrile (2 ml) was stirred for 1 minute at room temperature until a creamy suspension formed. Sonication during the process. (2R) -2-[(4S) -2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl] -N-[(1S)-in anhydrous acetonitrile (2.5 ml) under nitrogen. 2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl] pent-4-enamide (650 mg, 1.5 mmol), 1-bromo-3-fluoro To this stirred solution of -4-phenoxybenzene (Preparation 10) (587 mg, 2.26 mmol) and N-ethylmorpholine (348 μL, 3.0 mmol) was added by Pasteur pipette. The mixture was purged with nitrogen and then heated at reflux for 16 hours. After cooling, the mixture was poured into ethyl acetate (100 ml), washed with 5% aqueous citric acid (30 ml), saturated aqueous sodium chloride (50 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography (dilution with dichloromethane: ether) to give (2R, 5E) -2-[(4S) -2,2-dimethyl-5-oxo-1,3- as light yellow foams. Dioxolan-4-yl] -N-[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl} propyl] -5- (3-fluoro 4-phenoxyphenyl) pent-4-enamide (210 mg, 22%) was obtained ¹ H NMR showed that an alkene isomer is also present A mixture of alkenes was used for the next step (see b below). .

b) ethanol: ethyl acetate = (2R, 5E) -2-[(4S) -2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-in 5: 1 (10 ml)- N-[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl} propyl] -5- (3-fluoro-4-phenoxyphenyl) pent A solution of -4-enamide (210 mg, 0.34 mmol) was hydrogenated at 3 bar and 10% palladium over charcoal (20 mg) at 20 ° C. for 3 hours The mixture was filtered through an arbocell filtration aid and depressurized Concentrated under to give (2R) -2-[(4S) -2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl] -N-[(1S) -2,2- as a colorless solid Dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl} propyl] -5- (3-fluoro-4-phenoxyphenyl) pentanamide (103 mg, 49%) was obtained. It was used in Example 9 without purification.

<Production example 16>

(2R) -2-[(4S) -2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl] -N-[(1S) -2,2-dimethyl-1-({ [(1R) -1-phenylethyl] amino} carbonyl} propyl] -5- (3-methyl-4-phenyl) phenyl] pentanamide

a) According to the method of Preparation Example 15 a), (2R) -2-[(4S) -2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl] -N-[(1S ) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl] pent-4-enamide (Preparation 14) (860 mg, 2.0 mmol) was diluted to acetonitrile. 1-bromo-3-methyl-4-phenylbenzene in 740 mg, 3.0 mmol) was reacted for 16 hours under reflux under a palladium catalyst. After cooling, the mixture was partitioned between ethyl acetate (3 x 50 ml) and saturated aqueous sodium hydrogen carbonate (50 ml). The combined organic solution was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography (elution to dichloromethane: methanol = 97.5: 2.5) to give a pale yellow foam, mainly as (2R, 5E) -2-[(4S) -2,2-dimethyl-5-oxo-1. , 3-dioxolan-4-yl] -N-[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl} propyl] -5-[( 3-methyl-4-phenyl)] pent-4-enamide (480 mg, 40%) ¹ H NMR shows that an alkene isomer is also present A mixture of alkenes is used in the next step (b below) Reference).

b) (2R, 5E) -2-[(4S) -2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl] -N-[(1S)-in ethanol (20 ml) 2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl} propyl] -5-[(3-methyl-4-phenyl)] pent-4-enamide (480 mg , 0.80 mmol), were hydrogenated at 10% palladium over charcoal (48 mg) for 4 hours at 3 bar 20 ° C. The mixture was filtered through an arbocell filtration aid and concentrated under reduced pressure to give (2R) as a cream solid. -2-[(4'S) -2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl] -N-[(1S) -2,2-dimethyl-1-({[(1R ) -1-phenylethyl] amino} carbonyl} propyl] -5-[(3-methyl-4-phenyl) phenyl] pentanamide (440 mg, 92%) was obtained and used in Example 10 without purification. It was.

<Example 37 / Production Example 17>

(3R) -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl} propyl] amino} carbonyl) -6-[( 3-fluoro-4-phenyl) phenyl] hexanoic acid

Step a) of the method of Preparation Example 3 (using 1-bromo-3-fluoro-4-phenylbenzene instead of 1-bromo-3-methyl-4-phenylbenzene) and b) were carried out as colorless rubber. tert-butyl (3R, 5E) -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl] amino} carbonyl) -6- [3-fluoro- (4-phenyl) phenyl] hex-5-enoate (997 mg, 83%) was obtained. ¹ H NMR shows that there are also two alkene isomers, (5Z) and (4E). A mixture of alkenes was used for the next step.

Tert-butyl (3R) -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl] amino} carbonyl as colorless foam ) -6- [3-fluoro- (4-phenyl) phenyl] -hexanoate (702 mg, 72%)

Elemental Analysis of C ₃₇ H ₄₇ FN ₂ O ₄

Found: C, 73.66; H, 7.88; N, 4.64;

Theoretical values: C, 73.73; H, 7.86; N, 4.65%

c) tert-butyl (3R) -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl, according to the method of Preparation Example 1) ) Propyl] amino} carbonyl) -6- [3-fluoro- (4-phenyl) phenyl] -hexanoate (650 mg, 1.08 mmol) was treated with trifluoroacetic acid at 20 ° C. for 4 hours to give the title Compound (470 mg, 80%) was obtained.

m.p. 165-168 ° C (after trituration with diisopropyl ether)

R _f 0.38 (ether: hexane: acetic acid = 70: 30: 1)

Elemental Analysis of C ₃₃ H ₃₉ FN ₂ O ₄

Found: C, 72.52; H, 7.24; N, 5.09;

Theoretical value: C, 72.50; H, 7. 19; N, 5.12%

FTIRυ _max. (KBR disk) 3300, 3070, 3030, 2965, 1710, 1633, 1543, 764, 700 cm ^-1

<Production example 18>

To methyl (3R) -3-[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl} propyl] amino} carbonyl)-(2S)- Methoxy-6-[(3-methyl-4-phenyl) phenyl] hexanoate

a) According to the method of Preparation Example 15a), methyl (2R, 3R) -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl) in acetonitrile ] Amino} carbonyl) propyl] amino} carbonyl) -2-ethoxy-hex-5-enoate (415 mg, 0.96 mmol), (Preparation Example 8a) (396 mg, 1.37 mmol) were prepared using 1-bromo. The reaction was carried out with 3-methyl-4-phenylbenzene (340 mg, 0.92 mmol) at reflux under a palladium catalyst for 16 hours. After cooling, the mixture was poured into ethyl acetate (70 ml), washed with 5% aqueous citric acid (20 ml), saturated aqueous sodium chloride (50 ml), dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography (elution with hexanes: ethyl acetate) to give (2S, 3R, 5E) -3-({[(1S) -2,2-dimethyl-1-({ [(1R) -1-phenylethyl] amino} carbonyl) propyl] amino} carbonyl) -2-ethoxy-6-[(3-methyl-4-phenyl) phenyl] hex-5-enoate (415 mg, 75%). ¹ H NMR shows that there are also two alkene isomers, (5Z) and (4E). A mixture of alkenes was used for the next step (see b below).

b) (2S, 3R, 5E) -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) in ethanol (20 ml) Propyl] amino} carbonyl) -2-ethoxy-6-[(3-methyl-4-phenyl) phenyl] hex-5-enoate (415 mg, 0.70 mmol) was added to a bar of charcoal ( 40 mg) was hydrogenated at 10% palladium above for 2 hours. This mixture was filtered through an arbocell filtration aid and concentrated under reduced pressure. The residue was dissolved in cyclohexane and evaporated to (2 times) methyl (2S, 3R) -3-[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl as colorless foam). ] Amino} carbonyl) propyl] amino} carbonyl) -2-ethoxy-6- (3-fluoro-4-phenoxyphenyl) hexanoate (384 mg, 91%) was obtained, which was not purified. It was used in Example 12.

<Production example 19A>

tert-butyl (3R) -3-({[(1S) -2,2-dimethyl-1-({[(1S) -2-methoxy-1-phenylethyl] amino} carbonyl) propyl] amino} Carbonyl) -6- [3-methyl- (4-phenyl) phenyl] hexanoate

a) (2R) -2- [2- (tert-butoxy) -2-oxoethyl] pent-4-enoic acid (2.13 g, 10 mmol), N in anhydrous dichloromethane (50 ml) at 0 ° C. nitrogen. -tert-leucine benzyl ester (2.834 g, 11 mmol) (N. Moss et al., J. Med. Chem., 1996, 39, 2178), N-methylmorpholine (2.40 ml, 22 mmol) And N- (dimethylaminopropyl) -N'-ethylcarbodiimide (2.298 g, 12 mmol) was added to a stirred mixture of 1-hydroxybenzotriazole hydrate (1.836 g, 12 mmol). This mixture was slowly warmed to room temperature in a cold bath. After 20 hours the mixture is poured into ethyl acetate (250 ml), washed with 5% aqueous citric acid (2 x 100 ml), saturated aqueous sodium hydrogen carbonate (2 x 70 ml) and brine (70 ml) and dried (MgSO ₄ ) It concentrated under reduced pressure. The residual oil was crystallized by the addition of pentane. The solid was filtered and dried to afford tert-butyl (3R) -3-({[(1S) -2,2-dimethyl-1- (benzyloxycarbonyl) propyl] amino} carbonyl) hex-5 as a colorless solid. -Enoate (4.068 g, 97%) was obtained.

b) tert-butyl (3R) -3-({[(1S) -2,2-dimethyl-1- (benzyloxycarbonyl) propyl] amino} carbonyl) hex according to the method of Preparation Example 3 a) -5-Enoate (2.085 g, 5.0 mmol) for 16.5 hours under palladium catalyst in acetonitrile using 3-methyl-4-phenylbromobenzene (1.855 g, 7.5 mmol) and N-ethylmorpholine as base Reacted for a while. Finished as above, and repeatedly purified by flash chromatography (eluting with hexane: ether = 4: 1 in the first column and toluene: ether = 20: 1 in the second column) as light yellow rubber, predominantly tert-butyl (3R). , 5E) -3-({[(1S) -2,2-dimethyl-1- (benzyloxycarbonyl) propyl] amino} carbonyl) -6- [3-methyl- (4-phenyl) phenyl] hex -5-Enoate (2.205 gm, 75%) was obtained. ¹ H NMR shows that there are also two alkene isomers, (5Z) and (4E). A mixture of alkenes was used for the next step (see c below).

c) ethanol / water = tert-butyl (3R, 5E) -3-({[(1S) -2,2-dimethyl-1- (benzyloxycarbonyl) propyl] amino} in 4: 1 (44 ml) Carbonyl) -6- [3-methyl- (4-phenyl) phenyl] hex-5-enoate (2.205 g, 3.78 mmol) was hydrogenated at 10% palladium over charcoal at 3 bar room temperature for 6 hours. This mixture was filtered through an arbocell filtration aid and washed well with ethanol. The filtrate was concentrated under reduced pressure. The residue was dissolved in toluene to evaporate (three times), dissolved in ether to evaporate (twice), finally dissolved in ether and precipitated as an oil by addition of hexane. Solvent was removed under reduced pressure to give tert-butyl (3R) -3-({[(1S) -2,2-dimethyl-1- (carboxy) propyl] amino} carbonyl) -6- [3-methyl as colorless foam -(4-phenyl) phenyl] hexanoate (1.817 g, 97%) was obtained.

m.p. 51-56 ℃

d) tert-butyl (3R) -3-({[(1S) -2,2-dimethyl-1- (carboxy) propyl] amino} carbonyl) -6 in dry dichloromethane (5 ml) at 0 ° C. nitrogen. -[3-methyl- (4-phenyl) phenyl] hexanoate (496 mg, 1.0 mmol), (1S) -2-methoxy-1-phenylethylamine (151 mg, 1.0 mmol) (J. Amer. Chem. Soc., 1995, 177, 10885) and 7-Azabenzotriazol-1-yloxytris (pyrrolidino) phosphonium hexafluorophosphate in a stirred solution of collidine (267 μl, 2.0 mmol) (522 mg, 1.0 mmol) was added. After 1 hour the solution was stirred at 20 ° C. for 2.75 hours. The mixture was poured into ethyl acetate (70 ml) and washed sequentially with 5% aqueous citric acid (2 x 50 ml), saturated aqueous sodium hydrogen carbonate (2 x 50 ml) and brine (50 ml). This organic solution was dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with hexanes: ethyl acetate = 3: 1) to give tert-butyl (3R) -3-({[(1S) -2,2-dimethyl-1-({ [(1S) -2-methoxy-1-phenylethyl] amino} carbonyl) propyl] amino} carbonyl) -6- [3-methyl- (4-phenyl) phenyl] hexanoate (537 mg, 85 %) Was obtained.

<Production example 19B>

tert-butyl (3R) -3-({[(1S) -2,2-dimethyl-1-({[(1S) -2-methoxy-1-phenylethyl] amino} carbonyl) propyl] amino} Carbonyl) -6- [3-methyl- (4-phenyl) phenyl] hexanoate

a) 3-methyl-4-phenylbromobenzene was synthesized according to the following procedure.

5-bromo-2-iodo-toluene (5.01 g, 16.9 mmol), phenylboronic acid (2.26 g, 18.5 mmol) in acetone (60 ml), palladium acetate (190 mg, 0.85 mmol), triphenylphosphine (440 mg, 1.68 mmol) and 2M aqueous sodium carbonate (25 ml) were degassed and heated for 18 hours under reflux under nitrogen. This mixture was cooled and partitioned between ether (200 ml) and water (100 ml). The organic layer was washed with brine (100 ml), dried (MgSO ₄ ) and concentrated under reduced pressure to give a yellow oil. Purification by flash chromatography (eluting with hexanes) gave 3-methyl-4-phenylbromobenzene (3.298 g, 79%).

b) 3-methyl-4-phenyl in anhydrous tetrahydrofuran (30 ml) in a suspension of magnesium turnings (1.33 g, 50 mmol) in anhydrous tetrahydrofuran (23 ml) containing crystals of iodine under nitrogen. A solution of bromobenzene (12.36 mg, 50.0 mmol) was added dropwise under reflux with mechanical stirring. After the addition was finished the mixture was diluted with anhydrous tetrahydrofuran (55 ml) and heating continued for 1 hour. The arylmagnesium bromide solution was cooled to room temperature and then added dropwise by syringe to a solution of glutamine anhydride (6.27 g, 55 mmol) in tetrahydrofuran (125 ml) under -40 ° C nitrogen. After 90 minutes at -40 ° C the mixture was warmed to 0 ° C and hydrochloric acid (1M, 250 ml) was added. The mixture was extracted with ether (500 ml), washed with brine (200 ml), dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with dichloromethane: methanol = 95: 5) to give 5- (3-methyl-4-phenyl) phenyl-5-oxopentanoic acid (8.6 g, 60%) as light brown oil. Which was later crystallized.

m.p. 91-94 ℃

Elemental Analysis of C ₁₈ H ₁₈ O ₃

Found: C, 76.49; H, 6. 48;

Theoretical value: C, 76.57; H, 6.43%

c) Triethylsilane (1.4 ml) in a stirred solution of 5- (3-methyl-4-phenyl) phenyl-5-oxopentanoic acid (1.0 g, 3.5 mmol) in trifluoroacetic acid (5 ml) at 0 ° C. nitrogen. , 8.75 mmol) was added dropwise over 2 minutes. The mixture was then warmed to room temperature and stirred for 2 hours. This mixture was poured into water (20 ml) and extracted with dichloromethane (3 x 15 ml). The combined organic solution was washed with brine, dried (MgSO ₄ ) and concentrated under reduced pressure. The mixture was purified by flash chromatography (eluting with dichloromethane: methanol = 95: 5) to obtain 3: 1 of [5- (3-methyl-4-phenyl) phenyl] pentanoic acid and triethylsilanol (1.1 g). A mixture was obtained. This material was dissolved in hexane (5 ml) and sodium hydrogencarbonate (290 mg, 3.5 mmol) was added. The mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The solid residue was triturated with ethyl acetate and filtered to give [5- (3-methyl-4-phenyl) phenyl] pentanoate (820 mg, 80%). This material was treated with hydrochloric acid and the solvent was extracted to give the free acid as a viscous colorless rubber.

Elemental Analysis of C ₁₈ H ₂₀ O ₂

Found: C, 80.40; H, 7.59;

Theoretical value: C, 80.56; H, 7.51%

d) Oxalyl chloride (3.1 ml, 35.5) in a stirred solution of [5- (3-methyl-4-phenyl) phenyl] pentanoic acid (6.80 g, 25.3 mmol) in dichloromethane anhydrous (60 ml) at -10 ° C nitrogen. mmol) was added dropwise. Dimethylformamide (2 drops) was added and after 10 minutes the mixture was allowed to warm to room temperature. After 5 hours, this solution was concentrated under reduced pressure, and the residue was dissolved in anhydrous toluene and concentrated under reduced pressure (twice). The residue was dissolved in hexane (150 ml) and held for 17 hours, then filtered through an arbocell filtration aid to further wash the filter cake with hexane. The filtrate was concentrated under reduced pressure to give [5- (3-methyl-4-phenyl) phenyl] pentanoyl chloride (7.1 g, 97%).

N-butyllithium (9.92 ml, 2.5 in hexanes) in a solution of 4- (S) -benzyloxazolidin-2-one (4.39 g, 24.8 mmol) in anhydrous tetrahydrofuran (70 ml) at -70 ° C nitrogen. M, 24.8 mmol) was added dropwise over 15 minutes. The mixture was warmed to -50 ° C for 30 minutes and then recooled to -70 ° C. A solution of [5- (3-methyl-4-phenyl) phenyl] pentanoyl chloride (7.1 g, 24.8 mmol) in anhydrous tetrahydrofuran (10 ml) was added dropwise over 15 minutes. After 1 h, the mixture was warmed to 0 ° C. and 20% aqueous ammonium chloride (75 ml) was added. After stirring for 15 minutes, the mixture was extracted with ethyl acetate (250 ml), the organic phase was washed with water (3 x 250 ml), dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with pentane: ethyl acetate = 20: 1 to 2: 1) to give 4- (S) -benzyl-3-{[5- (3-methyl-4- as colorless oil). Phenyl) phenyl] pentanoyl} oxazolidin-2-one (9.66 g, 91%) was obtained.

Elemental Analysis of C ₂₈ H ₂₉ NO ₃ · 0.3CH ₂ Cl ₂

Found: C, 75.43; H, 6.65; N, 3.08;

Theoretical value: C, 75.03; H, 6.59; N, 3.09%

e) 4- (S) -benzyl-3-{[5- (3-methyl-4-phenyl) phenyl] pentanoyl} oxazolidin-2-one in anhydrous tetrahydrofuran (100 ml) at -75 ° C. To a stirred solution of (13.39 g, 31.3 mmol) was added dropwise a solution of sodium hexamethyldisilazide (31.3 ml, 1 M in tetrahydrofuran, 31.3 mmol) dropwise over 30 minutes. After 1 hour, a solution of tert-butyl bromoacetate (4.95 ml, 33.5 mmol) in anhydrous tetrahydrofuran (10 ml) was added dropwise over 20 minutes and the temperature was kept below -70 ° C. The mixture was stirred at this temperature for 2 hours and then warmed to −50 ° C. for 30 minutes at which point 20% aqueous ammonium chloride (150 ml) was added with rapid stirring. The mixture was warmed to 10 ° C and then poured into a mixture of ethyl acetate (400 ml) and water (200 ml). The organic phase was separated, washed with water (3 × 250 ml), dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography (elution to pentane: ether = 20: 1) to give tert-butyl (3R) -3-[(4- (S) -4-benzyl-2-oxo-1 as colorless oil. , 3-oxazolidin-3-yl) carbonyl] -6- (3-methyl-4-phenyl) phenyl) hexanoate (10.4 g, 61%) was obtained.

R _f 0.6 (pentane: ether = 1: 1)

Elemental Analysis of C ₃₄ H ₃₉ NO ₅ , 0.1 Ether, 0.2EtOAc

Found: C, 74.55; H, 7. 40; N, 2.44;

Theoretical value: C, 74.60; H, 7. 40; N, 2.47%

f) tert-butyl (3R) -3-[(4- (S) -4-benzyl-2-oxo-1,3-oxazoli in tetrahydrofuran: water (3: 1, 400 ml) at 0 ° C A solution of 30% aqueous hydrogen peroxide (12.75 ml, 114 mmol) was added to a solution of din-3-yl) carbonyl] -6- (3-methyl-4-phenyl) phenyl) hexanoate (10.3 g, 19.0 mmol). Added dropwise. Lithium hydroxide monohydrate (1.595 ml, 38.0 mmol) was then added in one portion. The mixture was stirred at 0 ° C for 2 h to 20 ° C for 1 h. The reaction mixture was recooled to 0 ° C. and a solution of sodium sulfite (15.56 g, 123.5 mmol) in water (80 ml) was added dropwise over 15 minutes. The mixture was quickly stirred at 0 ° C. for 2.5 h and then adjusted to pH 6 by addition of 2 M hydrochloric acid (ca. 8 ml). The mixture was concentrated to half volume under reduced pressure, acidified to pH 2 by addition of 2M hydrochloric acid and extracted with dichloromethane (400 ml and 2 × 200 ml). The combined extracts were dried (MgSO ₄ ) and concentrated under reduced pressure and the residue was purified by flash chromatography (eluent pentane: ether = 15: 1 followed by 1: 4 gradient) to give tert-butyl (3R) -3 as colorless oil. -(Carboxy) -6- (3-methyl-4-phenyl) phenyl) hexanoate (7.05 g, 97%) was obtained.

Elemental analysis for _{C 24 H 30 O 4 · 0.1H} 2 O

Found: C, 74.96; H, 8.06;

Theoretical value: C, 75.01; H, 7.92%

g) (2S) -amino-3,3-dimethyl-N-[(1S) -2-methoxy-1-phenylethyl] butanamide hydrochloride in anhydrous dichloromethane (82 ml) at 4 ° C. nitrogen (Preparation Example 1a) (6.78 g, 17.43 mmol, containing 1 molar equivalent of dioxane), tert-butyl (3R) -3- (carboxy) -6- (3-methyl-4-phenyl) phenyl) hexanoate (6.35 g, 16.6 mmol), N- (dimethylamino) in a stirring mixture of 1-hydroxy-1,2,3-benzotriazole hydrate (2.80 g, 20.75 mmol) and diisopropylethylamine (5.9 ml, 34.03 mmol) Propyl) -N'-ethylcarbodiimide hydrochloride (3.50 g, 18.26 mmol) was added. After 2 hours, the mixture was warmed to room temperature. After 17 h at rt, the mixture was poured into ethyl acetate (600 ml) and washed sequentially with 5% aqueous citric acid (2 x 250 ml), saturated aqueous sodium hydrogen carbonate (2 x 250 ml) and brine (200 ml) Dry (MgSO ₄ ) and concentrate under reduced pressure. The residue was dissolved in ether and evaporated to give tert-butyl (3R) -3-({[1S) -2,2-dimethyl-1-({[(1S) -2-methoxy-1-phenyl as colorless foam. Ethyl] amino} carbonyl) propyl] amino} carbonyl) -6- [3-methyl- (4-phenyl) phenyl] hexanoate (10.35 g, 99%).

Elemental Analysis of C ₃₉ H ₅₂ N ₂ O ₅ .0.04EtOAc

Found: C, 73.99; H, 8.31; N, 4.51;

Theoretical value: C, 74.38; H, 8.34; N, 4.43%

<Production example 20>

4-iodo-1- (3-methoxyphenyl) -2-methylbenzene

a) in tetrakis (triphenylphosphine) palladium (0) (9.77 gm, 9.25 mmol) under room temperature nitrogen in 2-bromo-5-nitrotoluene (40.0 gm, in 1,2-dimethoxyethane (600 ml) 185 mmol) was added. A solution of 3-methoxyphenylboronic acid (31.5 gm, 207 mmol) in ethanol (150 ml) was added. Finally 2M aqueous sodium carbonate (800 ml) was added and the mixture was heated under reflux for 18 hours with rapid mechanical stirring. After cooling, the mixture was partitioned between ethyl acetate and water and the organic phase was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. Purification by column chromatography on silica gel (eluting with hexanes: ethyl acetate = 98: 2 followed by 95: 5) gave 1- (3-methoxyphenyl) -2-methyl-4-nitrobenzene (40.55 gm, 90% )

b) Dissolve 1- (3-methoxyphenyl) -2-methyl-4-nitrobenzene (23.4 gm, 96 mmol) in a mixture of ethanol and ethyl acetate (3: 1, 470 ml) at 20 ° C. Hydrogenated at 10% palladium on charcoal (2.3 mg) for 2 hours. This mixture was filtered through an arbocell filtration aid and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to afford 4-amino-1- (3-methoxyphenyl) -2-methylbenzene (20.8 gm, 100%) as a pinkish brown oil.

c) A stirred solution of 4-amino-1- (3-methoxyphenyl) -2-methylbenzene (5.0 gm, 23.4 mmol) and iodine (2.97 gm, 25.8 mmol) in toluene (120 ml) was heated to 50 ° C. And iso-amyl nitrite (3.46 ml, 25.8 mmol) in toluene (50 ml) was added. The mixture was heated at 90 ° C. for 2 hours and cooled. Toluene was removed under reduced pressure, and the residue was dissolved in dichloromethane and washed with excess 5% aqueous sodium metabisulfite to remove iodine. The organic solution was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified repeatedly by flash chromatography (first column eluting with hexanes: ethyl acetate, then eluting with hexanes: ethyl acetate, second column eluting with hexanes) to give 4-iodo-1- (3-methoxy as a pale orange oil. Phenyl) -2-methylbenzene (5.63 gm, 74%) was obtained.

<Production example 21>

tert-butyl (3R) -3-({[(1S) -2,2-dimethyl-1-({[(1S) -2-methoxy-1-phenylethyl] amino} carbonyl) propyl] amino} Carbonyl) -6- [3'-methoxy-2-methylbiphen-4-yl) hexanoate

a) tert-butyl (3R) -3-({[(1S) -2,2-dimethyl-1- (benzyloxycarbonyl) propyl] amino} carbonyl) hex according to the method of Preparation Example 3 a) N- as the base while refluxing 5-5-enoate (2.085 g, 5.0 mmol) with 4-iodo-1- (3-methoxyphenyl) -2-methylbenzene (Preparation 20) (889.5 mg, 2.13 mmol) Ethyl morpholine was used to react for 14.5 hours under a palladium catalyst in acetonitrile. Finished as above, and repeatedly purified by flash chromatography (hexane: ethyl acetate = 10: 1) to give tert-butyl (3R, 5E) -3-({[(1S) -2, 2-dimethyl-1- (benzyloxycarbonyl) propyl] amino} carbonyl) -6- (3'-methoxy-2-methylbiphen-4-yl) hex-5-enoate (1.043 gm, 80% ) ¹ H NMR shows that there are also two alkene isomers, (5Z) and (4E). A mixture of alkenes was used for the next step (see b below).

b) tert-butyl (3R, 5E) -3-({[(1S) -2,2-dimethyl-1- (benzyloxycarbonyl) propyl] amino} carbonyl, according to the method of example 19 c) ) -6- (3'-methoxy-2-methylbiphen-4-yl] hex-5-enoate (1.040 g, 1.69 mmol) was hydrogenated in 10% palladium on charcoal to form tert-butyl ( 3R) -3-({[(1S) -2,2-dimethyl-1- (carboxy) propyl] amino} carbonyl) -6- (3'methoxy-2-methylbiphen-4-yl) hexano Obtained (664 mg, 75%).

c) tert-butyl (3R) -3-({[(1S) -2,2-dimethyl-1- (carboxy) propyl] amino} carbonyl) -6- (according to the method of example 19 d) 3'methoxy-2-methylbiphen-4-yl) hexanoate (660 mg, 1.26 mmol) was reacted with (1S) -2-methoxy-1-phenylethylamine (190 mg, 1.260 mmol). Finished as above and purified by flash chromatography (hexane: ethyl acetate = 3: 1) to give tert-butyl (3R) -3-({[(1S) -2,2-dimethyl-1 as colorless foam. -({[(1S) -2-methoxy-1-phenylethyl] amino} carbonyl) propyl] amino} carbonyl) -6- [3'-methoxy-2-methylbiphen-4-yl) hexa Noate (672 mg, 81%) was obtained.

R _f 0.16 (hexane: ethyl acetate = 4: 1)

Elemental Analysis of C ₄₀ H ₅₄ N ₂ O ₆ · ½H ₂ O

Found: C, 72.15; H, 8.21; N, 4.17;

Theoretical value: C, 71.93; H, 8. 30; N, 4.19%

<Production example 22>

(2R) -5-{[4- (4-cyanophenyl) -3-methyl] phenyl} -2-[(4S) -2,2-dimethyl-5-oxo-1,3-dioxolane-4 -Yl] -N-[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl] pentanamide

a) According to the method of Preparation Example 15 a), (2R) -2-[(4S) -2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl] -N-[(1S ) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl] pent-4-enamide (Preparation 14) (430 mg, 1.0 mmol) was added to 1- (4-cyanophenyl) -4-iodo-2-methylbenzene (Preparation Example 23) (479 mg, 1.5 mmol) was reacted for 16 hours under a palladium catalyst in acetonitrile. After cooling, the mixture was partitioned between ethyl acetate (3 x 30 ml) and saturated aqueous sodium hydrogen carbonate (30 ml). The combined organic solution was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with dichloromethane: methanol = 97.5: 2.5) to give mainly pale yellow foam as (2R, 4E) -5-{[4- (4-cyanophenyl) -3-methyl] phenyl. } -2-[(4S) -2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl] -N-[(1S) -2,2-dimethyl-1-({[( 1R) -1-phenylethyl] amino} carbonyl) propyl] pent-4-enamide (403 mg, 65%) was obtained. ¹ H NMR shows that alkene isomers are also present. A mixture of alkenes was used for the next step (see b below).

b) (2R, 4E) -5-{[4- (4-cyanophenyl) -3-methyl] phenyl} -2-[(4S) -2,2-dimethyl-5- in ethanol (70 ml) Oxo-1,3-dioxolan-4-yl] -N-[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl] pent- 4-enamide (403 mg, 0.65 mmol) was hydrogenated at 10% palladium over charcoal (40 mg) at 3 bar 20 ° C. for 5.5 hours. The mixture was filtered through an arbocell filtration aid and concentrated under reduced pressure to afford (2R) -5-{[4- (4-cyanophenyl) -3-methyl] phenyl} -2-[(4S)-as a colorless solid. 2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl] -N-[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino } Carbonyl) propyl] pentanamide (384 mg, 61%) was obtained and used in Example 17 without purification.

<Production example 23>

1- (4-cyanophenyl) -4-iodo-2-methylbenzene

a) 2-bromo-5-nitrotoluene (7.05 gm, 32.67 mmol), 4-cyanophenylboronic acid in 1,2-dimethoxyethane (240 ml) under room temperature nitrogen (Tet. Lett., 1993 , 34, 8237]) (6.0 gm, 40.83 mmol), cesium fluoride (11.02 gm, 72.53 mmol) and tri- (2-methylphenyl) phosphine (1.0 gm, 3.27 mmol) were stirred for 40 minutes. Tris (dibenzylideneacetone) dipalladium (1.50 gm, 1.63 mmol) was added and stirred at room temperature for 10 minutes and then heated at 80 ° C. for 4 hours. After cooling, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate. The organic phase was separated, washed with water, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to afford crude 1- (4-cyanophenyl) -2-methyl-4-nitrobenzene (9.78 gm), which was further Used without purification.

b) 1- (4-cyanophenyl) -2-methyl-4-nitrobenzene (9.7 gm, 40.76 mmol) is dissolved in a mixture of methanol and dichloromethane (1: 1, 400 ml) and 3 bar 20 ° C. Hydrogenated at 10% palladium over charcoal (970 mg) for 18 hours. This mixture was filtered through an arbocell filtration aid and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane: ethyl acetate = 20: 1 to 1: 1 gradient eluting) to give 4-amino-1- (4-cyanophenyl) -2-methylbenzene (2.5 gm as brown oil). , 30%).

c) a suspension of 4-amino-1- (4-cyanophenyl) -2-methylbenzene (250 mg, 1.2 mmol) in concentrated hydrochloric acid (1.3 ml) and water (1.6 ml) at 0 ° C. was water (1 ml Treated with a solution of sodium nitrite (183 mg, 2.65 mmol) over 10 minutes. After the mixture was stirred for 20 minutes, a solution of potassium iodide (840 mg, 5.06 mmol) in water (2 ml) was added over 10 minutes. The resulting mixture was heated at 90 ° C. for 2 hours and then cooled. The residue was extracted with dichloromethane (3 x 30 ml) and washed with 5% aqueous sodium metabisulfite (4 x 30 ml) to remove iodine. The organic solution was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane: ethyl acetate = 20: 1 eluting with 10: 1 gradient) to give 1- (4-cyanophenyl) -4-iodo-2-methylbenzene (as white solid). 263 mg, 69%).

<Production example 24>

(2R) -5-{[4- (3-cyanophenyl) -3-methyl] phenyl} -2-[(4S) -2,2-dimethyl-5-oxo-1,3-dioxolane-4 -Yl] -N-[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl] pentanamide

a) (2R) -2-[(4S) -2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl] -N-[(1S in anhydrous acetonitrile (3 ml) under nitrogen ) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl] pent-4-enamide (Preparation 14) (430 mg, 1.0 mmol), 1- (3-cyanophenyl) -4-iodo-2-methylbenzene (Preparation 25) (457 mg, 1.50 mmol), tri- (2-methylphenyl) phosphine) (30 mg, 0.10 mmol) and N- To a stirred solution of ethylmorpholine (190 μl, 1.5 mmol) was added palladium acetate (12.2 mg, 0.050 mmol). The mixture was purged with nitrogen and then heated at reflux for 14 hours. After cooling, the mixture was poured into ethyl acetate (100 ml) and washed with water (100 ml), 0.5 M aqueous sodium monophosphate (50 ml) and saturated aqueous sodium hydrogen carbonate (50 ml). The organic solution was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane: ethyl acetate = 3: 1 to 1: 1 gradient eluting) to give a pale yellow foam which was mainly (2R, 4E) -5-{[4- (3-cyanophenyl)- 3-methyl] phenyl} -2-[(4S) -2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl] -N-[(1S) -2,2-dimethyl-1 -({[(1R) -1-phenylethyl] amino} carbonyl) propyl] pent-4-enamide (385 mg, 62%) was obtained. ¹ H NMR shows that alkene isomers are also present. A mixture of alkenes was used for the next step (see b below).

R _f 0.27 (Dichloromethane: ethyl acetate = 10: 1)

Elemental analysis for _{C 38 H 43 N 3 O 5} · 0.25H 2 O

Found: C, 72.88; H, 7.05; N, 6.63;

Theoretical value: C, 72.88; H, 7.00; N, 6.71%

b) (2R, 4E) -5-{[4- (3-cyanophenyl) -3-methyl] phenyl} -2-[(4S) -2,2-dimethyl-5- in ethanol (35 ml) Oxo-1,3-dioxolan-4-yl] -N-[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl] pent- 4-enamide (359 mg, 0.58 mmol) was hydrogenated at 10% palladium over charcoal (35 mg) at 3 bar 20 ° C. for 6 hours. This mixture was filtered through an arbocell filtration aid, concentrated under reduced pressure and boiled with ethyl acetate followed by diethyl ether. The residual oil was purified by flash chromatography (hexane: ethyl acetate = 5: 1 to 1: 1 gradient eluting), then triturated with pentane and crystallized to give (2R) -5-{[4- (3-sia) as a white solid. Nophenyl) -3-methyl] phenyl} -2-[(4S) -2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl] -N-[(1S) -2,2 -Dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl] pentanamide (139 mg, 38%) was obtained, which was used in Example 19.

Elemental Analysis of C ₃₈ H ₄₅ N ₃ O ₅

Found: C, 72.99; H, 7. 36; N, 6.75;

Theoretical value: C, 73.17; H, 7. 27; N, 6.74%

<Production example 25>

1- (3-cyanophenyl) -4-iodo-2-methylbenzene

a) 1,2-dimethoxyethane (150 ml) in a solution of tetrakis (triphenylphosphine) palladium (0) (2.35 gm, 2.04 mmol) in 1,2-dimethoxyethane (100 ml) under room temperature nitrogen A solution of 2-bromo-5-nitrotoluene (8.82 gm, 40.83 mmol) in was added. A solution of 3-cyanophenylboronic acid (J.Med. Chem., 1997, 40, 4208) (9.0 gm, 61.25 mmol) in ethanol (45 ml) was added and stirred for 10 minutes. Finally, 2M aqueous sodium carbonate (234 ml) was added and the mixture was heated at reflux for 18 hours. After cooling, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate. The organic phase was washed with water and dried (Na ₂ SO ₄ ), concentrated under reduced pressure and triturated with diethyl ether to give 1- (3-cyanophenyl) -2-methyl-4-nitrobenzene (8.48 gm, 87% as brown solid). )

b) 1- (3-cyanophenyl) -2-methyl-4-nitrobenzene (3.0 gm, 12.61 mmol) and tin (II) chloride dihydrate are suspended in ethanol (30 ml) at 70 ° C. for 30 minutes. Heated. After cooling, the mixture was poured onto ice and neutralized by addition of sodium hydrogen carbonate. This mixture was then extracted with dichloromethane (3 x 50 ml). The combined organic phases were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to afford 4-amino-1- (3-cyanophenyl) -2-methylbenzene (1.8 gm, 69%) as a yellow oil.

c) A suspension of 4-amino-1- (3-cyanophenyl) -2-methylbenzene (2.5 gm, 12.0 mmol) in concentrated hydrochloric acid (13 ml) and water (16 ml) was added water (10 ml) at 0 ° C. Treated with a solution of sodium nitrite (1.83 gm, 26.5 mmol) over 10 minutes. After the mixture was stirred for 20 minutes, a solution of potassium iodide (8.40 gm, 50.6 mmol) in water (20 ml) was added over 10 minutes. The resulting mixture was heated at 80 ° C. for 2 hours and then cooled. The residue was extracted with dichloromethane and the combined organic extracts were washed with excess 5% aqueous sodium metabisulfite to remove iodine. The organic solution was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane: ethyl acetate gradient eluted at 20: 1 to 10: 1) to give 1- (3-cyanophenyl) -iodo-2-methylbenzene (1.105 gm, 29 as a white solid. %) Was obtained.

<Production example 26>

(2R) -5-{[4- (3-carbamoylphenyl) -3-methyl] phenyl} -2-[(4S) -2,2-dimethyl-5-oxo-1,3-dioxolane- 4-yl] -N-[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl] pentanamide

a) (2R) -2-[(4S) -2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl] -N-[(1S in anhydrous acetonitrile (3 ml) under nitrogen ) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl] pent-4-enamide (Preparation 14) (366 mg, 0.58 mmol), 1- (3-carbamoylphenyl) -4-iodo-2-methylbenzene (Preparation 27) (300 mg, 0.89 mmol), tri- (2-methylphenyl) phosphine) (27 mg, 0.09 mmol) and N Palladium acetate (10.4 mg, 0.042 mmol) was added to a stirred solution of ethylmorpholine (115 μl, 0.89 mmol). The mixture was purged with nitrogen and then heated at reflux for 3 hours. Palladium acetate (10.4 mg, 0.042 mmol) was added to reflux for 60 minutes. After further addition of palladium acetate (10.4 mg, 0.042 mmol) at 60 minute intervals, the reaction was refluxed for 8 hours. The reaction was cooled and diluted with acetonitrile (10 ml) and filtered through an arbocell filtration aid and washed with ethyl acetate (100 ml). The filtrate was washed with 5% aqueous sodium hydrogen carbonate (50 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography (dichloromethane: ethyl acetate = gradient eluting at 10: 1 to 1: 1) to give (2R, 4E) -5-{[4- (3-carbamoylphenyl) as a yellow foam. -3-methyl] phenyl} -2-[(4S) -2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl] -N-[(1S) -2,2-dimethyl- 1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl] pent-4-enamide (175 mg, 32%) was obtained.

Elemental Analysis of C ₃₈ H ₄₅ N ₃ O ₆ 0.2EtOAc

Found: C, 70.59; H, 7. 16; N, 6. 42;

Theoretical value: C, 70.89; H, 7.14; N, 6.39%

b) (2R, 4E) -5-{[4- (3-carbamoylphenyl) -3-methyl] phenyl} -2-[(4S) -2,2-dimethyl-5 in ethanol (50 ml) -Oxo-1,3-dioxolan-4-yl] -N-[(1S) -2,2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl] pent 4-Enamide (160 mg, 0.25 mmol) was hydrogenated at 10% palladium over charcoal (25 mg) at 3 bar 20 ° C. for 8 hours. This mixture was filtered through an arbocell filtration aid, concentrated under reduced pressure and boiled with ethyl acetate followed by diethyl ether. The residue was purified by flash chromatography (hexane eluting with ethyl acetate = 5: 1 to 1: 3 eluting) and then boiled with diethyl ether to give (2R) -5-{[4- (3- Carbamoylphenyl) -3-methyl] phenyl} -2-[(4S) -2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl] -N-[(1S) -2 , 2-dimethyl-1-({[(1R) -1-phenylethyl] amino} carbonyl) propyl] pentanamide (82 mg, 51%) was obtained, which was used in Example 20.

Elemental Analysis of C ₃₈ H ₄₇ N ₃ O ₆ · 0.25EtOAc

Found: C, 70.26; H, 7.59; N, 6.36;

Theoretical value: C, 70.56; H, 7. 44; N, 6.33%

<Production example 27>

1- (3-carbamoylphenyl) -4-iodo-2-methylbenzene

To a solution of 1- (3-cyanophenyl) -4-iodo-2-methylbenzene (1.27 gm, 4.0 mmol) in ethanol (50 ml) was added potassium hydroxide (1.21 gm, 21.6 mmol) for 16 hours. Heated under reflux. After cooling, the mixture was diluted with water (100 ml) and extracted with ethyl acetate (3 x 50 ml). The combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to afford crude product (1.08 gm). The crude product (540 mg) was subjected to flash chromatography (dilution of dichloromethane: saturated methanolic ammonia 100: 2.5, followed by dichloromethane: ethyl acetate 1: 1, then dichloromethane: ethyl acetate: acetic acid 100: 100: 4). After purification, boiling with ethanol, ethyl acetate and diethyl ether gave 1- (3-carbamoylphenyl) -4-iodo-2-methylbenzene (310 mg, 46%) as a pale yellow solid.

<Production example 28>

tert-butyl (3R) -3-[({({[(1S) -2-methoxy-1-phenylethyl] amino} carbonyl)-[(1S) -2-methyl] -1-propyl} amino ) Carbonyl] -6- [3-methyl- (4-phenyl) phenyl] hexanoate

a) N-tert-butoxycarbonyl-L-valine (868 mg, 4.0 mmol) was prepared according to the method of Preparation Example 19 a) (1S) -2-methoxy-1-phenylethylamine (604 mg, 4.0 mmol) for 72 hours. This mixture was concentrated under reduced pressure and partitioned between ethyl acetate (200 ml) and water (200 ml). The organic layer was washed with 5% aqueous citric acid (100 ml), saturated aqueous sodium hydrogen carbonate (100 ml), dried (MgSO ₄ ) and concentrated under reduced pressure. The product was triturated with diisopropyl ether, filtered and dried to give (2S) -tert-butyl- (butoxycarbonyl) amino-N-[(1S) -2-methoxy-1-phenylethyl]-as a colorless solid. 3-methylbutanamide (1.11 g, 79%) was obtained.

b) (2S) -tert-butyl- (butoxycarbonyl) amino-N-[(1S) -2-methoxy-1-phenyl in a mixture of anhydrous dichloromethane (15 ml) and dioxane (15 ml) Ethyl] -3-methylbutanamide (1.11 g, 3.17 mmol) was dissolved and cooled to 4 ° C. Hydrogen chloride was bubbled through the solution until a saturated solution formed. After stirring at 4 ° C. for 4 hours, the solution was concentrated under reduced pressure. The residue was boiled with dichloromethane to give (2S) -amino-N-[(1S) -2-methoxy-1-phenylethyl] -3-methylbutanamide hydrochloride (948 mg, 104%) as a pale yellow foam. )

c) Following the method of Preparation Example 2, (2R) -2- [2- (tert-butoxy) -2-oxoethyl] pent-4-enoic acid (646 mg, 3.02 mmol) (from b) (2S) -amino-N-[(1S) -2-methoxy-1-phenylethyl] -3-methylbutanamide hydrochloride (908 mg, 3.17 mmol) for 1 h at 4 ° C followed by 18 at 20 ° C The reaction was carried out for a time. The mixture was concentrated under reduced pressure and partitioned between ethyl acetate (100 ml) and saturated aqueous sodium hydrogen carbonate (100 ml). This layer was separated and the aqueous layer was extracted again with ethyl acetate (100 ml). The combined organic phases were dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with dichloromethane: methanol = 98: 2) to give tert-butyl (3R) -3-[({({[(1S) -2-methoxy-1- as white solid). Phenylethyl] amino} carbonyl)-(1S) -2-methyl-1-propyl] amino} carbonyl) hex-5-enoate (1.08 g, 80%) was obtained.

d) tert-butyl (3R) -3-[(from (c)) under a palladium catalyst in acetonitrile according to the method of Preparation Example 15 a) ({({[(1S) -2-methoxy- 1-phenylethyl] amino} carbonyl)-(1S) -2-methyl-1-propyl] amino} carbonyl) hex-5-enoate (1.08 g, 2.42 mmol) 4-iodo-2-methyl It was reacted with -1-phenylbenzene (Preparation Example 29) (1.07 g, 3.63 mmol) for 18 hours. After cooling, the mixture is diluted with ethyl acetate (200 ml) and washed sequentially with 5% aqueous citric acid (50 ml), saturated aqueous sodium hydrogen carbonate (50 ml) and saturated aqueous brine (50 ml) and dried ( Na ₂ SO ₄ ) was concentrated under reduced pressure. The residue was purified by flash chromatography (dilution of dichloromethane: ethyl acetate = 30: 1 to 3: 1) to give (3R, 5E) -3-[({({[(1S) -2- as light brown foam). Methoxy-1-phenylethyl] amino} carbonyl)-(1S) -2-methyl-1-propyl] amino} carbonyl) -6- [3-methyl- (4-phenyl) phenyl] hex-5- Enoate (980 mg, 66%) was obtained.

Elemental Analysis of C ₃₈ H ₄₈ N ₂ O ₅

Found: C, 74.43; H, 7.85; N, 4.57;

Theoretical value: C, 74.48; H, 7.90; N, 4.57%

e) tert-butyl (3R, 5E) -3-[({({[(1S) -2-methoxy-1-phenylethyl] amino} carbonyl) in ethanol (50 ml) 3 bar of)-(1S) -2-methyl-1-propyl] amino} carbonyl) -6- [3-methyl- (4-phenyl) phenyl] hex-5-enoate (930 mg, 1.51 mmol) Hydrogenated at 10 ° C. over 10% palladium on charcoal (75 mg) for 17 hours. This mixture was filtered through an arbocell filtration aid and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with pentane: ethyl acetate = 10: 1 to 2: 1) and triturated with diethyl ether to give tert-butyl (3R) -3-[({({[ (1S) -methoxy-1-phenylethyl] amino} carbonyl)-(1S) -2-methyl-1-propyl] amino} carbonyl) -6- [3-methyl- (4-phenyl) phenyl] Hexanoate (748 mg, 81%) was obtained, which was used in Example 21.

Elemental Analysis of C ₃₈ H ₅₀ N ₂ O ₅

Found: C, 74.39; H, 8. 24; N, 4.59;

Theoretical value: C, 74.32; H, 8. 27; N, 4.61%

<Production example 29>

4-iodo-2-methyl-1-phenylbenzene

a) According to the method of Preparation 25 a), dimethoxy using 2-bromo-5-nitrotoluene (15 gm, 69.4 mmol) with phenyl boronic acid (12.7 gm, 104.1 mmol) as 2M aqueous sodium carbonate as the base The treatment was carried out for 16 hours under a palladium catalyst in ethane. After cooling, the mixture was separated and the organic phase was diluted with diethyl ether and washed with water (twice). The organic layer was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with hexanes then hexanes: ethyl acetate = 95: 5) to afford 2-methyl-4-nitro-1-phenylbenzene (12.7 gm, 86%) as a yellow solid.

R _f 0.33 (hexane: ethyl acetate = 95: 5)

b) Hydrogenation of 2-methyl-4-nitro-1-phenylbenzene (12.7 gm, 60 mmol) in ethanol (260 ml) at 10% palladium over charcoal (1.27 gm) for 2 h at 3 ° C. It was. This mixture was filtered through an arbocell filtration aid and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to afford 4-amino-2-methyl-1-phenylbenzene (10.49 gm, 95%) as a pinkish brown oil.

c) stirred solution of 4-amino-2-methyl-1-phenylbenzene (10.49 gm, 57.2 mmol) in diiodomethane (100 ml) with iso-amyl nitrile (27 ml, 200. 2 mmol) Treatment over minutes The mixture was heated at 75 ° C. for 45 minutes and then at 65 ° C. for 1 hour. After cooling, the mixture was concentrated under reduced pressure (95 ° C./30 mmHg), and the residue was purified by flash chromatography (eluting with hexane) to give 4-iodo-2-methyl-1-phenylbenzene (as oil). 11.6 gm, 66%).

<Production example 30>

tert-butyl (3R) -3-({[({[(1S) -2-methoxy-1-phenylethyl] amino} carbonyl)-(1S) -2-phenylethyl] amino} carbonyl)- 6- [3-methyl- (4-phenyl) phenyl] hexanoate

a) According to the method of Preparation 19 a), N-tert-butoxycarbonyl-1-phenylalanine (1.06 mg, 4.0 mmol) was added to (1S) -2-methoxy-1-phenylethylamine (604 mg, 4.0 mmol) for 72 hours. This mixture was concentrated under reduced pressure and partitioned between ethyl acetate (200 ml) and water (200 ml). The organic layer was washed with 5% aqueous citric acid (100 ml), saturated aqueous sodium hydrogen carbonate (100 ml), dried (MgSO ₄ ) and concentrated under reduced pressure. The product was triturated with diisopropyl ether, filtered and dried to afford (2S) -tert- (butoxycarbonyl) amino-N-[(1S) -2-methoxy-1-phenylethyl] -3- as a white solid. Phenylpropanamide (1.28 g, 81%) was obtained.

m.p. 133-134 ℃

R _f 0.76 (dichloromethane: methanol: concentrated aqueous ammonia = 90: 10: 1)

b) (2S) -tert- (butoxycarbonyl) amino-N-[(1S) -2-methoxy-1-phenylethyl] in a mixture of anhydrous dichloromethane (15 ml) and dioxane (15 ml). 3-phenylpropanamide (1.28 g, 3.2 mmol) was dissolved and cooled to 4 ° C. Hydrogen chloride was bubbled through the solution with stirring until a saturated solution formed. After stirring at 4 ° C. for 4 hours, the solution was concentrated under reduced pressure. The residue was boiled with dichloromethane to give (2S) -amino-N-[(1S) -2-methoxy-1-phenylethyl] -3-phenylpropanamide hydrochloride (1.11 g, 103%) as a pale yellow foam. )

c) According to the method of Preparation Example 2, (2R) -2- [2- (tert-butoxy) -2-oxoethyl] pent-4-enoic acid (658 mg, 3.07 mmol) was obtained from (b) above. Of) (2S) -amino-N-[(1S) -2-methoxy-1-phenylethyl] -3-phenylpropanamide hydrochloride (1.08 mg, 3.23 mmol) at 4 ° C. for 1 hour followed by 20 ° C. Reacted for 18 hours. The mixture was concentrated under reduced pressure and partitioned between ethyl acetate (100 ml) and saturated aqueous sodium hydrogen carbonate (100 ml). This layer was separated and the aqueous layer was extracted again with ethyl acetate (100 ml). The combined organic layers were dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was triturated with diisopropyl ether and filtered to give tert-butyl (3R) -3-({[({[(1S) -2-methoxy-1-phenylethyl] amino} carbonyl)-as a white solid. (1S) -2-phenylethyl] amino} carbonyl) hex-5-enoate (1.35 g, 85%) was obtained.

d) tert-butyl (3R) -3- (from c) under a palladium catalyst in acetonitrile according to the method of Preparation Example 15 a) ({[({[(1S) -2-methoxy- 1-phenylethyl] amino} carbonyl)-(1S) -2-phenylethyl] amino} carbonyl) hex-5-enoate (1.35 mg, 2.73 mmol) was converted to 4-iodo-2-methyl-1- It was reacted with phenylbenzene (Preparation 29) (1.21 g, 4.09 mmol) for 18 hours. After cooling, the mixture was diluted with ethyl acetate (200 ml) and washed with 5% aqueous citric acid (50 ml), saturated aqueous sodium hydrogen carbonate (50 ml) and saturated brine (50 ml) and dried (Na ₂ SO). ₄ ) concentrated under reduced pressure. The residue was purified by flash chromatography (dichloromethane: ethyl acetate = 50: 1 then gradient eluting at 5: 1) to give (3R, 5E) -3-[({({[(1S) -2) as a light brown foam. -Methoxy-1-phenylethyl] amino} carbonyl)-(1S) -2-phenylethyl] amino} carbonyl) -6- [3-methyl- (4-phenyl) phenyl] hex-5-enoate (1.1 g, 61%) was obtained.

Elemental Analysis of C ₄₂ H ₄₈ N ₂ O ₅

Found: C, 76.10; H, 7. 27; N, 4.20;

Theoretical value: C, 76.33; H, 7. 32; N, 4.24%

e) tert-butyl (3R, 5E) -3-[({({[(1S) -2-methoxy-1-phenylethyl] amino} carbonyl)-(1S) -2 in ethanol (100 ml) -Phenylethyl] amino} carbonyl) -6- [3-methyl- (4-phenyl) phenyl] hex-5-enoate (1.03 g, 1.56 mmol) on 3 bar 20 charcoal (125 mg) at 20 ° C. Hydrogenated at 10% palladium for 18 hours. This mixture was filtered through an arbocell filtration aid and concentrated under reduced pressure. The residue was purified by flash chromatography (pentane: ethyl acetate = 10: 1 then gradient elution to 2: 1) and triturated with diethyl ether to give tert-butyl (3R) -3-({[({ [(1S) -2-methoxy-1-phenylethyl] amino} carbonyl)-(1S) -2-phenylethyl] amino} carbonyl) -6- [3-methyl- (4-phenyl) phenyl] Hexanoate (980 mg, 95%) was obtained, which was used in Example 22.

Elemental Analysis of C ₄₂ H ₅₀ N ₂ O ₅

Found: C, 76.03; H, 7. 70; N, 4.25;

Theoretical value: C, 76.10; H, 7. 60; N, 4.23%

<Production example 31>

tert-butyl- (3R) -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1- (4-pyridyl) ethylamino] carbonyl} propyl] amino} Carbonyl) -6-[(3-methyl-4-phenyl) phenyl] hexanoate

Example 25a) According to the method of tert-butyl (3R) -3-({[(1S) -1- (carboxy) -2,2-dimethylpropyl] amino} carbonyl) -6-[(3 -Methyl-4-phenyl) phenyl] hexanoate (Preparation 19c) (497 mg, 1.0 mmol) was combined with (R)-(+)-1- (4-pyridine) ethylamine (122 mg, 1.0 mmol). After reacting for 2.5 hours at room temperature, the resultant was treated as above to obtain tert-butyl- (3R) -3-({[(1S) -2,2-dimethyl-1-({[(1R)) as a white solid. -1- (4-pyridyl) ethylamino] carbonyl} propyl] amino} carbonyl) -6-[(3-methyl-4-phenyl) phenyl] hexanoate (460 mg, 77%) was obtained.

R _f 0.21 (hexane: ethyl acetate = 1: 2)

<Example 38 / Production Example 32>

(3R) -3-({[(1S) -2,2-dimethyl-1-{[(1R) -1- (3-pyridyl) ethylamino] carbonyl} propyl] amino} carbonyl) -6 -[(3-methyl-4-phenyl) phenyl] hexanoic acid

a) According to the method of example 25 a) tert-butyl (3R) -3-({[(1S) -1- (carboxy) -2,2-dimethylpropyl] amino} carbonyl) -6- [ 3-methyl- (4-phenyl) phenyl] hexanoate (Preparation 19c) (497 mg, 1.0 mmol) was added to (R)-(+)-1- (3-pyridyl) ethylamine (122 mg, 1.0 mmol), and then at room temperature for 2.5 hours, then treated as above and purified by flash chromatography (hexane: ethyl acetate = 4: 1 then gradient to 100% ethyl acetate) and tert-butyl as colorless foam. -(3R) -3-({[(1S) -2,2-dimethyl-1-({[(1R) -1- (3-pyridyl) ethylamino] carbonyl} propyl] amino} carbonyl) -6- [3-methyl- (4-phenyl) phenyl] hexanoate (537 mg, 89%) was obtained.

b) Hydrogen chloride under nitrogen at 0 ° C. in tert-butyl- (3R) -3-({[(1S) -2,2-dimethyl-1-({[( Of 1R) -1- (3-pyridyl) ethylamino] carbonyl} propyl] amino} carbonyl) -6- [3-methyl- (4-phenyl) phenyl] hexanoate (285 mg, 0.47 mmol) The solution was bubbled through, stirred for 3 h at 0 ° C., and then concentrated under reduced pressure The residue was dissolved in methanol (3 ml) and diethyl ether (3 ml) was added and the mixture was filtered. The filtrate was concentrated under reduced pressure The residue was dissolved in methanol (3 ml) and concentrated under reduced pressure by addition of toluene (3 ml) Finally diethyl ether (5 ml) was added to the residue and sonicated. Treatment gave a white solid which was filtered and dried to give the title compound as a white solid (338 mg, 65%).

Elemental analysis for _{C 33 H 41 N 3 O 4} · HCl · 1.25H 2 O

Found: C, 65.78; H, 7. 26; N, 6.72;

Theoretical value: C, 65.74; H, 7.63; N, 6.76%

<Production example 33>

(2R) -N-[(1S) -1- (carboxy) -2,2-dimethylpropyl] -2-[(4S) -2,2-dimethyl-5-oxo-1,3-dioxolane-4 -Yl] -5-[(3-methyl-4-phenyl) phenyl] pentanamide

a) (4S) -4-[(1R) -1-carboxy-but-3-enyl] -2,2-dimethyl-1,3-diox according to the method of Preparation Example 2 Solan-5-one (2.39 g, 11.20 mmol) was reacted with L-tert-leucine benzyl ester hydrochloride (3.03 g, 11.76 mmol) at 4 ° C. for 1 hour and then at 20 ° C. for 17 hours. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate (200 ml), washed with 0.5 M aqueous sodium monophosphate (2 x 200 ml), 5% saturated sodium bicarbonate (200 ml) and water and dried (MgSO ₄ ) Concentrated under reduced pressure. The residue was purified by flash chromatography (hexane: ethyl acetate = 10: 1 then gradient eluting at 1: 1) to give (2R) -N-[(1S) -1-[(benzyloxy) carbonyl as a white solid. ] -2,2-dimethylpropyl] -2-[(4S) -2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl] pent-4-enamide (4.06 g, 87% )

Elemental Analysis of C ₂₃ H ₃₁ NO ₆

Found: C, 66.13; H, 7. 50; N, 3.36;

Theoretical value: C, 66.17; H, 7. 48; N, 3.35%

b) (2R) -2-[(4S) -2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl] -N-{(1S in anhydrous acetonitrile (15 ml) under nitrogen. ) -2,2-dimethyl-1-[(benzyloxy) carbonyl] propyl} pent-4-enamide (2.0 g, 4.8 mmol), 4-iodo-2-methyl-1-phenylbenzene (Preparation Example Palladium acetate (58 mg, 0.24 mmol) was added to a stirred solution of 29) (2.1 g, 7.20 mmol) and N-ethylmorpholine (920 μl, 7.20 mmol) and the reflux continued. The mixture was purged with nitrogen and then heated at reflux. Since palladium precipitates after 1 hour, palladium acetate (58 mg, 0.24 mmol) is added and the reflux is continued. After 2 hours more 58 mg of palladium acetate was added. After 2 hours more, tri- (2-methylphenyl) phosphine (304 mg, 1.0 mmol) and palladium acetate (58 mg, 0.24 mmol) were added to the mixture and refluxed for 2 hours, then again tri- (2 -Methylphenyl) phosphine (304 mg, 1.0 mmol) and palladium acetate (58 mg, 0.24 mmol) were added to reflux the mixture for 8 hours. The reaction was cooled, diluted with ethyl acetate (200 ml) and water (200 ml) and filtered through an arbocell filtration aid to remove palladium. This layer was separated and the organic layer was washed with water (2 × 100 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was purified by flash chromatography. Purification was first chromatographed (dichloromethane: ethyl acetate = 50: 1 then gradient elution to 15: 1) to give a yellow gum. Again purified by flash chromatography (hexane: diethyl ether = 10: 1 then gradient eluting at 1: 1) and triturated with pentane: diethyl ether to give (2R, 4E) -N-{(1S)-as a white solid. 1-[(benzyloxy) carbonyl] -2,2-dimethylpropyl} -2-[(4S) -2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl] -5- [(3-methyl-4-phenyl) phenyl] pent-4-enamide (710 mg, 25%) was obtained.

Elemental Analysis of C ₃₆ H ₄₁ NO ₆

Found: C, 73.96; H, 7.02; N, 2.41;

Theoretical value: C, 74.08; H, 7.08; N, 2.40%

c) (2R, 4E) -N-{(1S) -1-[(benzyloxy) carbonyl] -2,2-dimethylpropyl} -2-[(4S) -2,2 in ethanol (150 ml) -Dimethyl-5-oxo-1,3-dioxolan-4-yl] -5-[(3-methyl-4-phenyl) phenyl] pent-4-enamide (1.24 gm, 2.12 mmol) 3 bar room temperature Was hydrogenated at 10% palladium on charcoal (100 mg) for 6 hours. This mixture was filtered through an arbocell filtration aid and concentrated under reduced pressure. The residue was boiled with diethyl ether to give (2R) -N-[(1S) -1- (carboxy) -2,2-dimethylpropyl] -2-[(4S) -2,2-dimethyl as a colorless foam. -5-oxo-1,3-dioxolan-4-yl] -5-[(3-methyl-4-phenyl) phenyl] pentanamide (1.08 gm, 103%) was obtained.

Elemental Analysis of C ₂₉ H ₃₇ NO ₆ 0.3H ₂ O

Found: C, 69.50; H, 7.69; N, 2.69;

Theoretical value: C, 69.52; H, 7.56; N, 2.80%

<Production example 34>

(2R) -N-[(1S) -1- (carboxy) -2,2-dimethylpropyl] -2-[(4S) -2,2-dimethyl-5-oxo-1,3-dioxolane-4 -Yl] -5-[(3'-methoxy-2-methylbiphen-4-yl) propyl] pentanamide

a) (2R) -N-[(1S) -1-[(benzyloxy) carbonyl] -2,2-dimethylpropyl] -2 under a palladium catalyst in acetonitrile according to the method of Preparation Example 15 a) 4- [iodine]-((4S) -2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl] pent-4-enamide (Preparation 32a) (1.0 g, 2.4 mmol) It was reacted with -1- (3-methoxyphenyl) -2-methylbenzene (Preparation Example 20) (1.16 g, 3.59 mmol) for 16 hours. After cooling, the mixture was partitioned between ethyl acetate (3 x 75 ml) and saturated aqueous sodium hydrogen carbonate (75 ml). The combined organic solution was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with dichloromethane: diethyl ether = 97.5: 2.5) to give (2R, 4E) -N-{(1S) -1-[(benzyloxy) carbonyl] -2 as a solid. , 2-dimethylpropyl} -2-[(4S) -2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl] -5-[(3'-methoxy-2-methylbifen -4-yl) propyl] pent-4-enamide (1.08 mg, 74%) was obtained. ¹ H NMR shows that alkene isomers are also present. A mixture of alkenes was used for the next step (see b below).

b) (2R, 4E) -N-{(1S) -1-[(benzyloxy) carbonyl] -2,2-dimethylpropyl} -2-[(4S) -2,2 in ethanol (75 ml) -Dimethyl-5-oxo-1,3-dioxolan-4-yl] -5-[(3'-methoxy-2-methylbiphen-4-yl) phenyl] pent-4-enamide (534 mg, 0.87 mmol) was hydrogenated at 10% palladium on charcoal (50 mg) at 5 ° C. for 3 bars at 5.75 h. The mixture was filtered through an arbocell filtration aid, concentrated under reduced pressure and boiled with ethyl acetate to give (2R) -N-[(1S) -1- (carboxy) -2,2-dimethylpropyl] -2 as a white solid. -[(4S) -2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl] -5-[(3'-methoxy-2-methylbiphen-4-yl) propyl] pentane Amide (384 mg, 61%) was obtained and used in Examples 31 and 31 without purification.

Claims (38)

A substance which is a compound of formula (I) or a pharmaceutically acceptable salt thereof or a solvate thereof. <Formula I> Where R ¹ is H, OH, C _1-4 alkyl, C _1-4 alkoxy or C _2-4 alkenyl, R ² is fluoro, indolyl, imidazolyl, SO ₂ (C _1-4 alkyl), C _5-7 cycloalkyl, or OH, SH, CONH ₂ , CO ₂ H, NH ₂ or NHC which may be protected C _1-6 alkyl which may be substituted by (= NH) NH ₂ groups, C _5-7 cycloalkyl which may be substituted by C _1-6 alkyl, or OH, C _1-6 alkoxy, which may be protected, Benzyl which may be substituted by benzyloxy or benzylthio, Any protecting group for the OH, SH, CONH ₂ , NH ₂ or NHC (= NH) NH ₂ group is selected from C _1-6 alkyl, benzyl, C _1-6 alkanoyl, and for any of the CO ₂ H The protecting group is selected from C _1-6 alkyl or benzyl, R ³ , R ⁵ and R ⁶ are each independently selected from H and F, R ⁴ is CH ₃ , Cl or F, X is HO or HONH, Y is direct bond or 0, Z is a group of formula a or formula b, <Formula a> <Formula b> [Wherein R ¹⁰ is C _1-4 alkyl, C _1-4 alkoxymethyl, hydroxy (C _2-4 alkyl), carboxy (C _2-4 alkyl) or (amino or dimethylamino) C _2-4 alkyl , R ¹¹ is phenyl, naphthyl or pyridyl, which may be substituted by up to 3 substituents independently selected from halo and methyl, R ¹⁴ is H, OH, CH ₃ or halo] Ar is a group of the formula c, d or e. <Formula c> <Formula d> <Formula e> [Wherein A is N or CR ¹² , B is N or CR ¹³ , Provided that both A and B are not N at the same time, R ⁷ and R ⁹ are each independently H or F, R ⁸ , R ¹² and R ¹³ are H, CN, C _1-6 alkyl, hydroxy (C _1-6 alkyl), hydroxy (C _1-6 alkyl) alkoxy, C _1-6 alkoxy (C _1-6 Alkoxy, (amino or dimethylamino) C _1-6 alkyl, CONH ₂ , OH, halo, C _1-6 alkoxy, (C _1-6 alkoxy) methyl, piperazinylcarbonyl, piperidinyl, C (NH ₂ ) = NOH or C (= NH) = NHOH, provided that at least two of R ⁸ , R ¹² and R ¹³ are H; The material of claim 1, wherein R ¹ is H, OH, C _1-4 alkyl or C _1-4 alkoxy. The compound of claim 1, wherein R ² is C, which may be substituted by indolyl, C _1-6 alkylthio, SO ₂ (C _1-4 alkyl), C _5-7 cycloalkyl, OH or SH. _A substance that is C _5-7 cycloalkyl, or benzyl, which may be substituted by _1-6 alkyl, C _1-6 alkyl. 4. The compound of claim 1, wherein Z is represented by formula a, [Wherein R ¹⁰ is C _1-4 alkyl, C _1-4 alkoxymethyl or hydroxy (C _2-4 alkyl) and R ¹¹ is substituted by up to 3 substituents independently selected from halo and methyl Phenyl or pyridyl], or Phosphorus substance. 5. The material of claim 1, wherein R ³ is H. 6. 6. The material of claim 1, wherein R ⁴ is F when Y is O, and R ⁴ is Cl or CH ₃ when Y is a direct bond. 7. The material of claim 1, wherein R ⁵ is H. ⁸ . 8. The material of claim 1, wherein R ⁶ is H. ⁹ . 9. The material of claim 1, wherein Ar is a group of formula c: 10. <Formula c> Where A is CR ¹² and B is CR ¹³ R ⁷ and R ⁹ are each independently H or F, R ⁸ and R ¹³ are each independently H, F, Cl, CN, CONH ₂ , CH ₃ or OCH ₃ , R ¹² is H, C _1-6 alkyl, CN, hydroxy (C _2-6 alkyl), (amino or dimethylamino) C _2-6 alkyl, CONH ₂ , OH, halo, C _1-6 alkoxy, (C _1-6 alkoxy) methyl, piperazinylcarbonyl, piperidinyl, C (NH ₂ ) = NOH or C (= NH) = NHOH. The material of claim 1, wherein R ¹ is H, OH, n-propyl or ethoxy. _11. C _1-6 alkyl, C _1- , as claimed in any one of claims 1 to 10, wherein R ² can be substituted by OH, SO ₂ (C _1-4 alkyl) or C _5-7 cycloalkyl. _{6 A} substance that is cyclohexyl, or benzyl, which may be substituted by alkyl. The compound of any one of claims 1-11, wherein Z is represented by formula a, Wherein R ¹⁰ is C _1-4 alkyl, C _1-4 alkoxymethyl or hydroxy (C _2-4 alkyl) and R ¹¹ is phenyl, pyridin-4-yl or pyridin-3-yl , or Phosphorus substance. 13. The material of claim 1, wherein Ar is a group of formula c. <Formula c> Where A is CR ¹² , B is CR ¹³ , and R ⁷ , R ⁸ and R ⁹ are H. The material of claim 1, wherein R ¹ is H. 15. The compound of claim 1, wherein R ² is cyclohexylmethyl, isopropyl, 1-methylcyclohexyl, t-butyl, C (CH ₃ ) ₂ SO ₂ CH ₃ , benzyl or C (CH). ₃ ) material that is ₂ OH. 16. The compound of any of claims 1-15, wherein Z is of formula a, Wherein R ¹⁰ is CH ₃ , CH ₂ 0CH ₃ or CH ₂ OH, and R ¹¹ is phenyl, pyridin-4-yl or pyridin-3-yl; or Phosphorus substance. 17. The material of any of claims 1-16, wherein Ar is a group of formula c. <Formula c> Where A is CR ¹² , B is CR ¹³ , R ⁷ , R ⁸ and R ⁹ are H, R ¹² is H, C _1-6 alkyl, CN, hydroxy (C _2-6 alkyl), (amino or dimethylamino) C _2-6 alkyl, CONH ₂ , OH, halo, C _1-6 alkoxy, (C _1-6 alkoxy) methyl, C (NH ₂ ) = NOH or C (= NH) = NHOH, R ¹³ is H, OCH ₃ , CN, CONH ₂ , CH ₃ or F. 18. The material of any one of claims 1 to 17, wherein R ² is isopropyl, t-butyl or benzyl. 19. The compound of any of claims 1-18, wherein Z is Phosphorus substance. 20. The compound of any of claims 1-19, wherein Ar is phenyl, 3-methoxyphenyl, 4-cyanophenyl, 3-cyanophenyl, 3-carbamoylphenyl or 4-hydroxyamidinophenyl Phosphorus substance. 21. The material of any one of the preceding claims, wherein R ² is t-butyl. 22. The material of any one of the preceding claims, wherein Ar is phenyl or 3-methoxyphenyl. The compound of claim 1, wherein R ¹ is H, OH, n-propyl or ethoxy, R ² is t-butyl, isopropyl or benzyl, Z is of formula a, Wherein R ¹⁰ is CH ₃ , CH ₂ 0CH ₃ or CH ₂ OH, and R ¹¹ is phenyl, pyridin-4-yl or pyridin-3-yl; or ego, R ³ is H, R ⁴ is CH ₃ , Cl or F, R ⁵ is H, R ⁶ is H, Ar is phenyl, 3-methoxyphenyl, 4-cyanophenyl, 3-cyanophenyl, 3-carbamoylphenyl or 4-hydroxyamidinophenyl. The material of claim 1 which is a material substantially defined in the Examples herein and salts and solvent compounds thereof. A material according to claim 1 and salts thereof selected from the compounds of Examples 3, 4, 8, 14, 15, 16, 22, 29, 30, 31 and 32. A pharmaceutical composition comprising a compatibility adjuvant, diluent or carrier with a substance according to any one of claims 1 to 25. A substance according to any one of claims 1 to 25 for use as a medicament. The preparation of a medicament for the treatment of a condition mediated by MMP, in particular MMP-3 and / or MMP-12 and / or MMP-13. Usage. A MMP, in particular MMP-3 and / or MMP-12 and / or MMP-13, comprising administering an effective amount of a substance according to any of claims 1 to 25 or a composition according to claim 26. Method of treatment or prevention of a condition mediated by. A process for preparing a substance according to claim 1 wherein X is OH, comprising modifying the compound of formula II as X ₁ is a hydrolysis of a compound of formula II wherein X ₁ is a CO ₂ (t-butyl or methyl) residue. <Formula II> Where X ₁ is a group which may be modified with carboxy, The other substituents are as defined in claim 1. X is NHOH, comprising reacting a compound of Formula I, wherein X is OH, with a hydroxylamine or hydroxylamine derivative, and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , Y, Ar And Z is a process for the preparation of a material according to claim 1 as defined in claim 1. Reacting a compound of formula (I) wherein X is OH in the presence of a peptide coupling agent with O-allylhydroxyamine or a salt thereof to provide formula (III), followed by treatment with ammonium formate in the presence of a suitable catalyst Wherein X is NHOH and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , Y, Ar and Z are as defined in claim 1. <Formula III> X is NHOH, R ¹ is OH, and R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , Y, Ar and Z, comprising reacting a compound of Formula IV with hydroxylamine or a salt thereof A process for the preparation of a substance according to claim 1 as defined in claim 1. <Formula IV> Compounds of formula (V) are cross-coupled with compounds of formula (VI) in the presence of a catalyst to prepare compounds of formula (VIIa) and / or VIIb, followed by reduction of olefin residues and deprotection of protected acid residues X ₂ Wherein X is OH and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , Y, Ar and Z are prepared according to claim ^{1 as} defined in claim ¹ . Way. <Formula V> <Formula VI> <Formula VIIa> <Formula VIIb> Wherein X ₂ is a protected acid such as CO ₂ CH ₃ or (C0 ₂ ) (t-butyl) group, LG is a cross-coupling leaving group such as I, Br or OSO ₂ CF _3, and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , Y, Ar and Z are as defined in claim 1. A compound of formula II or a salt thereof or a solvent compound thereof. <Formula II> Wherein X ₁ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , Y, Ar and Z are as defined in claim 30. A compound of formula III: or a salt thereof or a solvent compound thereof. <Formula III> Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , Y, Ar and Z are as defined in claim 32. A compound of formula IV or a salt thereof or a solvent compound thereof. <Formula IV> Wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , Y, Ar and Z are as defined in claim 33. A compound of formula (VIIa) or (VIIb) or a salt thereof or a solvent compound thereof. <Formula VIIa> <Formula VIIb> Wherein X ₂ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , Y, Ar and Z are as defined in claim 34.